Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity

ABSTRACT

Chemical syntheses and medical uses of novel inhibitors of the uptake of monoamine neurotransmitters and pharmaceutically acceptable salts and prodrugs thereof, for the treatment and/or management of psychotropic disorders, anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric disorders, premenstrual dysphoric disorder, social phobia, social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, and/or premature ejaculation are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 11/565,451,entitled “SUBSTITUTED PHENETHYLAMINES WITH SEROTONINERGIC AND/ORNOREPINEPHRINERGIC ACTIVITY”, filed Nov. 30, 2006 now U.S. Pat. No.7,456,317, which claims priority to U.S. Provisional Application Nos.60/741,315, entitled “SUBSTITUTED PHENETHYLAMINES WITH SEROTONINERGICAND/OR NOREPINEPHRINERGIC ACTIVITY”, filed Dec. 1, 2005; and 60/841,366,entitled “SUBSTITUTED PHENETHYLAMINES WITH SEROTONINERGIC AND/ORNOREPINEPHRINERGIC ACTIVITY”, filed Aug. 30, 2006, all of which areincorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to inhibitors of the uptake ofmonoamine neurotransmitters and pharmaceutically acceptable salts andprodrugs thereof, the chemical synthesis thereof, and the medical use ofsuch compounds for the treatment and/or management of psychotropicdisorders, anxiety disorder, generalized anxiety disorder, depression,post-traumatic stress disorder, obsessive-compulsive disorder, panicdisorder, hot flashes, senile dementia, migraine, hepatopulmonarysyndrome, chronic pain, nociceptive pain, neuropathic pain, painfuldiabetic retinopathy, bipolar depression, obstructive sleep apnea,psychiatric disorders, premenstrual dysphoric disorder, social phobia,social anxiety disorder, urinary incontinence, anorexia, bulimianervosa, obesity, ischemia, head injury, calcium overload in braincells, drug dependence, and/or premature ejaculation.

2. Description of the Related Art

In an attempt to breakdown or to help solubilize chemicals and nutrientsthat have been absorbed into the blood, the human body expresses variousenzymes (e.g. the cytochrome P₄₅₀ enzymes or CYPs, esterases, proteases,reductases, dehydrogenases, and the like) that react with the chemicalsand nutrients to produce novel intermediates or metabolites. Some of themost common metabolic reactions of pharmaceutical compounds involve theoxidation of a carbon-hydrogen (C—H) bond to either a carbon-oxygen(C—O) or carbon-carbon (C—C) π-bond. The resultant metabolites may bestable or unstable under physiological conditions, and can havesubstantially different pharmacokinetic, pharmacodynamic, acute andlong-term toxicity profiles relative to the parent compounds. For mostdrugs, such oxidations are generally rapid and ultimately lead toadministration of multiple or high daily doses. There is therefore anobvious and immediate need for improvements of such drugs.

Chemical kinetics is the study of reaction rates. The activation energyE_(act) in chemistry is the energy that must be supplied to a system inorder to initiate a particular chemical process. In other words, this isthe minimum energy required for a specific chemical reaction to takeplace. A reaction will occur between two properly oriented molecules ifthey possess a minimum requisite energy. During the approach, the outershell electrons of each molecule will induce repulsion. Overcoming thisrepulsion requires an input of energy (i.e. the activation energy),which results from the heat of the system; i.e. the translational,vibrational, and rotational energy of each molecule. If sufficientenergy is available, the molecules may attain the proximity andorientation necessary to cause a rearrangement of bonds to form newsubstances.

The relationship between the activation energy and the rate of reactionmay be quantified by the Arrhenius equation which states that thefraction of molecules that have enough energy to overcome an energybarrier—those with energy at least equal to the activation energy,E_(act)—depends exponentially on the ratio of the activation to thermalenergy k=Ae^(−Eact/RT). In this equation, RT is the average amount ofthermal energy that molecules possess at a certain temperature T, whereR is the molar gas constant, k is the rate constant for the reaction andA (the frequency factor) is a constant specific to each reaction thatdepends on the probability that the molecules will collide with thecorrect orientation.

The transition state in a reaction is a short lived state (on the orderof 10⁻¹⁴ sec) along the reaction pathway during which the original bondshave stretched to their limit. By definition, the activation energyE_(act) for a reaction is the energy required to reach the transitionstate of that reaction. Reactions that involve multiple steps willnecessarily have a number of transition states, and in these instances,the activation energy for the reaction is equal to the energy differencebetween the reactants and the most unstable transition state. Once thetransition state is reached, the molecules can either revert, thusreforming the original reactants, or the new bonds form giving rise tothe products. This dichotomy is possible because both pathways, forwardand reverse, result in the release of energy. A catalyst facilitates areaction process by lowering the activation energy leading to atransition state. Enzymes are examples of biological catalysts thatreduce the energy necessary to achieve a particular transition state.

A carbon-hydrogen bond is by nature a covalent chemical bond. Such abond forms when two atoms of similar electronegativity share some oftheir valence electrons, thereby creating a force that holds the atomstogether. This force or bond strength can be quantified and is expressedin units of energy, and as such, covalent bonds between various atomscan be classified according to how much energy must be applied to thebond in order to break the bond or separate the two atoms.

The bond strength is directly proportional to the absolute value of theground-state vibrational energy of the bond. This vibrational energy,which is also known as the zero-point vibrational energy, depends on themass of the atoms that form the bond. The absolute value of thezero-point vibrational energy increases as the mass of one or both ofthe atoms making the bond increases. Since deuterium (D) is two-foldmore massive than hydrogen (H), it follows that a C-D bond is strongerthan the corresponding C—H bond. Compounds with C-D bonds are frequentlyindefinitely stable in H₂O, and have been widely used for isotopicstudies. If a C—H bond is broken during a rate-determining step in achemical reaction (i.e. the step with the highest transition stateenergy), then substituting a deuterium for that hydrogen will cause adecrease in the reaction rate and the process will slow down. Thisphenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE) andcan range from about 1 (no isotope effect) to very large numbers, suchas 50 or more, meaning that the reaction can be fifty, or more, timesslower when deuterium is substituted for hydrogen. High DKIE values maybe due in part to a phenomenon known as tunneling, which is aconsequence of the uncertainty principle. Tunneling is ascribed to thesmall size of a hydrogen atom, and occurs because transition statesinvolving a proton can sometimes form in the absence of the requiredactivation energy. A deuterium is larger and statistically has a muchlower probability of undergoing this phenomenon. Substitution of tritiumfor hydrogen results in yet a stronger bond than deuterium and givesnumerically larger isotope effects.

Discovered in 1932 by Urey, deuterium (D) is a stable andnon-radioactive isotope of hydrogen. It was the first isotope to beseparated from its element in pure form and is twice as massive ashydrogen, and makes up about 0.02% of the total mass of hydrogen (inthis usage meaning all hydrogen isotopes) on earth. When two deuteriumsbond with one oxygen, deuterium oxide (D₂O or “heavy water”) is formed.D₂O looks and tastes like H₂O but it has different physical properties.It boils at 101.41° C. and freezes at 3.79° C. Its heat capacity, heatof fusion, heat of vaporization, and entropy are all higher than H₂O. Itis also more viscous and is not as powerful a solvent as H₂O.

Tritium (T) is a radioactive isotope of hydrogen, used in research,fusion reactors, neutron generators and radiopharmaceuticals. Mixingtritium with a phosphor provides a continuous light source, a techniquethat is commonly used in wristwatches, compasses, rifle sights and exitsigns. It was discovered by Rutherford, Oliphant and Harteck in 1934 andis produced naturally in the upper atmosphere when cosmic rays reactwith H₂ molecules. Tritium is a hydrogen atom that has 2 neutrons in thenucleus and has an atomic weight close to 3. It occurs naturally in theenvironment in very low concentrations, most commonly found as T₂O, acolorless and odorless liquid. Tritium decays slowly (half-life=12.3years) and emits a low energy beta particle that cannot penetrate theouter layer of human skin. Internal exposure is the main hazardassociated with this isotope, yet it must be ingested in large amountsto pose a significant health risk.

When pure D₂O is given to rodents, it is readily absorbed and reaches anequilibrium level that is usually about eighty percent of theconcentration that is consumed by the animals. The quantity of deuteriumrequired to induce toxicity is extremely high. When 0 to as much as 15%of the body water has been replaced by D₂O, animals are healthy but areunable to gain weight as fast as the control (untreated) group. Between15 to 20% D₂O, the animals become excitable. At 20 to 25%, the animalsare so excitable that they go into frequent convulsions when stimulated.Skin lesions, ulcers on the paws and muzzles, and necrosis of the tailsappear. The animals also become very aggressive; males becoming almostunmanageable. At 30%, the animals refuse to eat and become comatose.Their body weight drops sharply and their metabolic rates drop far belownormal, with death occurring at 30 to 35% replacement. The effects arereversible unless more than thirty percent of the previous body weighthas been lost due to D₂O. Studies have also shown that the use of D₂Ocan delay the growth of cancer cells and enhance the cytotoxicity ofcertain antineoplastic agents.

Deuteration of pharmaceuticals to improve pharmacokinetics (PK),pharmacodynamics (PD), and toxicity profiles, has been demonstratedpreviously with some classes of drugs. For example, DKIE was used todecrease the hepatotoxicity of halothane by presumably limiting theproduction of reactive species such as trifluoroacetyl chloride.However, this method may not be applicable to all drug classes. Forexample, deuterium incorporation can lead to metabolic switching whichmay even give rise to an oxidative intermediate with a faster off-ratefrom an activating Phase I enzyme (e.g. cytochrome P₄₅₀ 3A4). Theconcept of metabolic switching asserts that xenogens, when sequesteredby Phase I enzymes, may bind transiently and re-bind in a variety ofconformations prior to the chemical reaction (e.g. oxidation). Thisclaim is supported by the relatively vast size of binding pockets inmany Phase I enzymes and the promiscuous nature of many metabolicreactions. Metabolic switching can potentially lead to differentproportions of known metabolites as well as altogether new metabolites.This new metabolic profile may impart more or less toxicity. Suchpitfalls are non-obvious and have not been heretofore sufficientlypredictable a priori for any drug class.

It has been hypothesized that the efficacy of venlafaxine (Effexor®) ismainly due to its ability to inhibit serotonin reuptake and,potentially, norepinephrine reuptake in neuronal cells. The latter ispurported to take effect only at high doses. The drug substance is soldas a 50/50 racemic mixture of R- and S-enantiomers. The mechanism ofaction of this drug has been extensively studied.

The benefits and shortcomings of this drug have been extensivelyreviewed as well. Some of these shortcomings can be traced tometabolism-related phenomena. Venlafaxine is converted in vivo byoxidative and conjugative degradation to multiple metabolites, at least48 of which are documented. The major metabolites include much phase Imetabolism leading to demethylation at the oxygen and/or nitrogencenters, and cyclohexyl ring hydroxylation, as well as significant phaseII metabolism including glucuronidation of the hydroxylated metabolites.Because this drug is metabolized by polymorphically-expressed isozymesof cytochrome P₄₅₀ including CYPs 2C19 and 2D6, and because it can actas an inhibitor of CYP2D6, its application in polypharmacy isnecessarily complex and has potential for adverse events. These CYPs areinvolved in the metabolism of many medications that are typicallyprescribed concurrently with venlafaxine. This phenomenon increasesinter-patient variability in response to polypharmacy. An example of thecritical need for improvement is the published interpatient variabilityobserved in “poor metabolizers” having either defective CYP2D6 allelesor total lack of CYP2D6 expression. These patients fail to convertvenlafaxine to its equipotent metabolite, O-desmethylvenlafaxine.Venlafaxine also suffers from a short half-life relative to the majorityof serotonin reuptake inhibitors. The half-life of venlafaxine in humansis ˜5 hours, while its active metabolite has a T_(1/2) of ˜11 hours. Asa consequence of its 5-11 hour pharmacological half-life, those takingvenlafaxine are at significant risk of SRI discontinuation symptoms ifthe drug is abruptly discontinued. Furthermore, in order to overcome itsshort half-life, the drug must be taken 2 (BID) or 3 (TID) times a day,which increases the probability of patient incompliance anddiscontinuance. Most other serotonin reuptake inhibitors (SRIs) havehalf-lives ≧24 hours. A 24-72 hour half-life is regarded as ideal forthis class of compounds by most clinicians. There is therefore anobvious and immediate need for improvements in the development ofmonoamine reuptake inhibitors such as paroxetine.

SUMMARY OF THE INVENTION

Disclosed herein are compounds of Formula 1:

or a single enantiomer, a mixture of the (+)-enantiomer and the(−)-enantiomer, a mixture of about 90% or more by weight of the(−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, amixture of about 90% or more by weight of the (+)-enantiomer and about10% or less by weight of the (−)-enantiomer, an individual diastereomer,a mixture of diastereomers, or a pharmaceutically acceptable salt,solvate, or prodrug thereof, wherein:

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,R₁₇, and R₁₈ are independently selected from the group consisting ofhydrogen, and deuterium;

R₁₉, R₂₀, and R₂₁ are independently selected from the group consistingof —CH₃, —CH₂D, —CHD₂, and —CD₃;

provided that compounds of Formula 1 contain at least one deuteriumatom; and provided that deuterium enrichment in compounds of Formula 1is at least about 1%.

Also disclosed herein are pharmaceutical compositions comprising acompound of Formula 1, a single enantiomer of a compound of Formula 1, amixture of the (+)-enantiomer and the (−)-enantiomer, a mixture of about90% or more by weight of the (−)-enantiomer and about 10% or less byweight of the (+)-enantiomer, a mixture of about 90% or more by weightof the (+)-enantiomer and about 10% or less by weight of the(−)-enantiomer, an individual diastereomer of a compound of Formula 1, amixture of diastereomers, or a pharmaceutically acceptable salt,solvate, or prodrug thereof, with a pharmaceutically acceptable carrier.

Further, disclosed herein are methods of eliciting, modulating and/orregulating the reuptake of monoamine neurotransmitters includingserotonin and/or norepinephrine.

In addition, disclosed herein are methods of treating a mammaliansubject having, suspected of having, or being prone to a disease orcondition, such as a disease or condition selected from the groupconsisting of anxiety disorder, generalized anxiety disorder,depression, post-traumatic stress disorder, obsessive-compulsivedisorder, panic disorder, a hot flash, senile dementia, migraine,hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathicpain, painful diabetic retinopathy, bipolar depression, obstructivesleep apnea, psychiatric disorders, premenstrual dysphoric disorder,social phobia, social anxiety disorder, urinary incontinence, anorexia,bulimia nervosa, obesity, ischemia, head injury, calcium overload inbrain cells, drug dependence, and/or premature ejaculation.

DETAILED DESCRIPTION OF THE INVENTION

Certain monoamine reuptake inhibitors are known in the art and are shownherein. Venlafaxine (Effexor®) is one such compound. The carbon-hydrogenbonds of venlafaxine contain a naturally occurring distribution ofhydrogen isotopes, namely ¹H or protium (about 99.9844%), ²H ordeuterium (about 0.0156%), and ³H or tritium (in the range between about0.5 and 67 tritium atoms per 10¹⁸ protium atoms). Increased levels ofdeuterium incorporation produce a detectable Kinetic Isotope Effect(KIE) that could affect the pharmacokinetic, pharmacologic and/ortoxicologic parameters of such monoamine reuptake inhibitors relative tocompounds having naturally occurring levels of deuterium. Aspects of thepresent invention disclosed herein describe a novel approach todesigning and synthesizing new analogs of these monoamine reuptakeinhibitors through chemical modifications and derivations of thecarbon-hydrogen bonds of the modulators and/or of the chemicalprecursors used to synthesize said modulators. Suitable modifications ofcertain carbon-hydrogen bonds into carbon-deuterium bonds may generatenovel monoamine reuptake inhibitors with unexpected and non-obviousimprovements of pharmacological, pharmacokinetic and toxicologicalproperties in comparison to the non-isotopically enriched monoaminereuptake inhibitors. This invention relies on the judicious andsuccessful application of chemical kinetics to drug design. Deuteriumincorporation levels in the compounds of the invention are significantlyhigher than the naturally-occurring levels and are sufficient to induceat least one substantial improvement as described herein.

Information has come to light that enables the judicious use ofdeuterium in solving the PD and Absorption, Distribution, Metabolism,Excretion, and Toxicological (ADMET) shortcomings for venlafaxine. Forexample, both N-methyl groups, the single O-methyl, and several sites onthe cyclohexyl ring of venlafaxine are now known to be sites ofcytochrome P₄₅₀ metabolism. The toxicities of all resultant metabolitesare not known. Furthermore, because polymorphically expressed CYPs suchas 2C19 and 2D6 oxidize venlafaxine, and because venlafaxine inhibitsthe polymorphically expressed CYP2D6, the prevention of suchinteractions decreases interpatient variability, decreases drug-druginteractions, increases T_(1/2), decreases the necessary C_(max), andimproves several other ADMET parameters. For example, the half-life ofthe parent drug of venlafaxine ranges from 3-7 hours. The equipotentmetabolite, O-demethylated venlafaxine, has a half-life averaging 11hours. Various deuteration patterns can be used to a) alter the ratio ofactive metabolites, b) reduce or eliminate unwanted metabolites, c)increase the half-life of the parent drug, and/or d) increase thehalf-life of active metabolites and create a more effective drug and asafer drug for polypharmacy, whether the polypharmacy be intentional ornot. High doses of venalxafine are often prescribed in order to reachlevels capable of inhibiting norepinephrine reuptake. Unfortunately,high doses are also associated with hypertension. Since these phenomenonare linked by the pharmaceutical agent rather than the pharmacologicaltarget, the two phenomena are theoretically separable by increasing thehalf-life thus allowing dosing in a range that lowers the C_(max) andthus may avoid triggering the mechanism leading to hypertension. Furtherillustrating this point, venlafaxine is known to display linear kineticsat the low end of the dose range, 75 mg/day, but displays non-linearkinetics at the high end of the dose range, ˜400 mg/day, as a result ofthe saturation of clearance mechanisms. This non-linearity produces anascending, rather than a flat, dose-response curve for venlafaxine. Thedeuteration approach has strong potential to slow metabolism through thepreviously saturated mechanism allowing linear, more predictable ADMETresponses throughout the dose range (which would also be lower via thisinvention). This leads to lesser interpatient variability of the typethat can lead to the hypertensive effects.

The deuterated analogs of this invention have the potential to uniquelymaintain the beneficial aspects of the non-isotopically enriched drugswhile substantially increasing the half-life (T_(1/2)), lowering themaximum plasma concentration (C_(max)) of the minimum efficacious dose(MED), lowering the efficacious dose and thus decreasing thenon-mechanism-related toxicity, and/or lowering the probability ofdrug-drug interactions. These drugs also have strong potential to reducethe cost-of-goods (COG) owing to the ready availability of inexpensivesources of deuterated reagents combined with previously mentionedpotential for lowering the therapeutic dose. The present inventors havediscovered that deuteration at the methylenedioxy moiety alone, and/ordeuteration at the methylenedioxy moiety plus deuteration of additionalsites found to be labile as a result of metabolic switching areeffective in achieving some of the objectives disclosed herein.

Thus, in one aspect, there are provided herein compounds having thestructural Formula 1:

or a single enantiomer, a mixture of the (+)-enantiomer and the(−)-enantiomer, a mixture of about 90% or more by weight of the(−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, amixture of about 90% or more by weight of the (+)-enantiomer and about10% or less by weight of the (−)-enantiomer, an individual diastereomer,a mixture of diastereomers, or a pharmaceutically acceptable salt,solvate, or prodrug thereof, wherein:

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,R₁₇, and R₁₈ are independently selected from the group consisting ofhydrogen, and deuterium;

R₁₉, R₂₀, and R₂₁ are independently selected from the group consistingof —CH₃, —CH₂D, —CHD₂, and —CD₃;

provided that compounds of Formula 1 contain at least one deuteriumatom; and provided that deuterium enrichment in compounds of Formula 1is at least about 1%.

Compounds of this invention have the potential to uniquely maintain thebeneficial aspects of non-isotopically enriched monoamine reuptakeinhibitors while substantially altering the half-life (T_(1/2)),lowering the maximum plasma concentration (C_(max)) of the minimumefficacious dose (MED), lowering the efficacious dose and thusdecreasing non-mechanism-related toxicities and/or lowering theprobability of drug-drug interactions. These drugs also have potentialto reduce the cost-of-goods (COG) due to a potential for lowering thetherapeutic dose when compared to the non-isotopically enrichedmonoamine reuptake inhibitors. In sum, many aspects of ADMET of thenon-isotopically enriched monoamine reuptake inhibitors aresubstantially improved by this invention.

In some embodiments, agents in the present invention will exposepatients to a maximum of about 0.000005% D₂O (can also be expressed asabout 0.00001% DHO). This quantity is a small fraction of the naturallyoccurring background levels of D₂O (or DHO) in circulation. This maximumexposure limit is obtained if all of the C-D bonds of thedeuterium-enriched drug are metabolized. However, because of the DKIE,most if not all, of the C-D bonds of the deuterium-enriched drug willnot be metabolized prior to excretion of said deuterium-enriched drugfrom the subject. Therefore, the actual exposure of the patient to D₂Owill be far less than the aforementioned maximum limit. As discussedabove, the levels of D₂O shown to cause toxicity in animals is muchgreater than even the maximum limit of exposure because of the deuteriumenriched drug. The deuterium-enriched compounds of the presentinvention, therefore, do not cause any additional toxicity because ofthe use of deuterium.

“Deuterium enrichment” refers to the percentage of incorporation ofdeuterium at a given site on the molecule instead of a hydrogen atom.For example, deuterium enrichment of 1% means that in 1% of molecules ina given sample a particular site is occupied by deuterium. Because thenaturally occurring distribution of deuterium is about 0.0156%,deuterium enrichment in compounds synthesized using non-enrichedstarting materials is about 0.0156%. In some embodiments, the deuteriumenrichment in the compounds of the present invention is greater than10%. In other embodiments, the deuterium enrichment in the compounds ofthe present invention is greater than 20%. In further embodiments, thedeuterium enrichment in the compounds of the present invention isgreater than 50%. In some embodiments, the deuterium enrichment in thecompounds of the present invention is greater than 70%. In someembodiments, the deuterium enrichment in the compounds of the presentinvention is greater than 90%.

“Isotopic enrichment” refers to the percentage of incorporation of aless prevalent isotope of an element at a given site on the moleculeinstead of the more prevalent isotope of the element. “Non-isotopicallyenriched” refers to a molecule in which the percentage of the variousisotopes is substantially the same as the naturally occurringpercentages.

In certain embodiments, the compound of Formula 1 contains about 60% ormore by weight of the (−)-enantiomer of the compound and about 40% orless by weight of (+)-enantiomer of the compound. In some embodiments,the compound of Formula 1 contains about 70% or more by weight of the(−)-enantiomer of the compound and about 30% or less by weight of(+)-enantiomer of the compound. In some embodiments, the compound ofFormula 1 contains about 80% or more by weight of the (−)-enantiomer ofthe compound and about 20% or less by weight of (+)-enantiomer of thecompound. In some embodiments, the compound of Formula 1 contains about90% or more by weight of the (−)-enantiomer of the compound and about10% or less by weight of the (+)-enantiomer of the compound. In someembodiments, the compound of Formula 1 contains about 95% or more byweight of the (−)-enantiomer of the compound and about 5% or less byweight of (+)-enantiomer of the compound. In some embodiments, thecompound of Formula 1 contains about 99% or more by weight of the(−)-enantiomer of the compound and about 1% or less by weight of(+)-enantiomer of the compound.

In certain other embodiments, the compound of Formula 1 contains about60% or more by weight of the (+)-enantiomer of the compound and about40% or less by weight of (−)-enantiomer of the compound. In someembodiments, the compound of Formula 1 contains about 70% or more byweight of the (+)-enantiomer of the compound and about 30% or less byweight of (−)-enantiomer of the compound. In some embodiments, thecompound of Formula 1 contains about 80% or more by weight of the(+)-enantiomer of the compound and about 20% or less by weight of(−)-enantiomer of the compound. In some embodiments, the compound ofFormula 1 contains about 90% or more by weight of the (+)-enantiomer ofthe compound and about 10% or less by weight of the (−)-enantiomer ofthe compound. In some embodiments, the compound of Formula 1 containsabout 95% or more by weight of the (+)-enantiomer of the compound andabout 5% or less by weight of (−)-enantiomer of the compound. In someembodiments, the compound of Formula 1 contains about 99% or more byweight of the (+)-enantiomer of the compound and about 1% or less byweight of (−)-enantiomer of the compound.

In certain embodiments, R₁ is hydrogen. In other embodiments, R₂ ishydrogen. In some embodiments, R₃ is hydrogen. In other embodiments, R₄is hydrogen. In yet other embodiments, R₅ is hydrogen. In still otherembodiments, R₆ is hydrogen. In yet other embodiments, R₇ is hydrogen.In yet other embodiments, R₈ is hydrogen. In still other embodiments, R₉is hydrogen. In still other embodiments, R₁₀ is hydrogen. In otherembodiments, R₁₁ is hydrogen. In some embodiments, R₁₂ is hydrogen. Inother embodiments, R₁₃ is hydrogen. In still other embodiments, R₁₄ ishydrogen. In yet other embodiments, R₁₅ is hydrogen. In yet otherembodiments, R₁₆ is hydrogen. In still other embodiments, R₁₇ ishydrogen. In yet other embodiments, R₁₈ is hydrogen.

In certain embodiments, R₁ is deuterium. In other embodiments, R₂ isdeuterium. In some embodiments, R₃ is deuterium. In other embodiments,R₄ is deuterium. In yet other embodiments, R₅ is deuterium. In stillother embodiments, R₆ is deuterium. In yet other embodiments, R₇ isdeuterium. In yet other embodiments, R₈ is deuterium. In still otherembodiments, R₉ is deuterium. In still other embodiments, R₁₀ isdeuterium. In other embodiments, R₁₁ is deuterium. In some embodiments,R₁₂ is deuterium. In other embodiments, R₁₃ is deuterium. In still otherembodiments, R₁₄ is deuterium. In yet other embodiments, R₁₅ isdeuterium. In yet other embodiments, R₁₆ is deuterium. In still otherembodiments, R₁₇ is deuterium. In yet other embodiments, R₁₈ isdeuterium.

In certain embodiments, R₁ is not hydrogen. In other embodiments, R₂ isnot hydrogen. In some embodiments, R₃ is not hydrogen. In otherembodiments, R₄ is not hydrogen. In yet other embodiments, R₅ is nothydrogen. In still other embodiments, R₆ is not hydrogen. In yet otherembodiments, R₇ is not hydrogen. In yet other embodiments, R₈ is nothydrogen. In still other embodiments, R₉ is not hydrogen. In still otherembodiments, R₁₀ is not hydrogen. In other embodiments, R₁₁ is nothydrogen. In some embodiments, R₁₂ is not hydrogen. In otherembodiments, R₁₃ is not hydrogen. In still other embodiments, R₁₄ is nothydrogen. In yet other embodiments, R₁₅ is not hydrogen. In yet otherembodiments, R₁₆ is not hydrogen. In yet other embodiments, R₁₇ is nothydrogen. In still other embodiments, R₁₈ is not hydrogen.

In certain embodiments, R₁ is not deuterium. In other embodiments, R₂ isnot deuterium. In some embodiments, R₃ is not deuterium. In otherembodiments, R₄ is not deuterium. In yet other embodiments, R₅ is notdeuterium. In still other embodiments, R₆ is not deuterium. In yet otherembodiments, R₇ is not deuterium. In yet other embodiments, R₈ is notdeuterium. In still other embodiments, R₉ is not deuterium. In stillother embodiments, R₁₀ is not deuterium. In other embodiments, R₁₁ isnot deuterium. In some embodiments, R₁₂ is not deuterium. In otherembodiments, R₁₃ is not deuterium. In still other embodiments, R₁₄ isnot deuterium. In yet other embodiments, R₁₅ is not deuterium. In yetother embodiments, R₁₆ is not deuterium. In yet other embodiments, R₁₇is not deuterium. In still other embodiments, R₁₈ is not hydrogen.

In further embodiments, R₁₉ is —CH₃. In other embodiments, R₂₀ is —CH₃.In still other embodiments, R₂₁ is —CH₃.

In further embodiments, R₁₉ is —CD₃. In other embodiments, R₂₀ is —CD₃.In still other embodiments, R₂₁ is —CD₃.

In further embodiments, R₁₉ is not —CH₃. In other embodiments, R₂₀ isnot —CH₃. In still other embodiments, R₂₁ is not —CH₃.

In further embodiments, R₁₉ is not —CD₃. In other embodiments, R₂₀ isnot —CD₃. In still other embodiments, R₂₁ is not —CD₃.

In another embodiment of the invention, there are providedpharmaceutical compositions comprising at least one of the compounds ofFormula 1, a single enantiomer of a compound of Formula 1, a mixture ofthe (+)-enantiomer and the (−)-enantiomer, a mixture of about 90% ormore by weight of the (−)-enantiomer and about 10% or less by weight ofthe (+)-enantiomer, a mixture of about 90% or more by weight of the(+)-enantiomer and about 10% or less by weight of the (−)-enantiomer, anindividual diastereomer of a compound of Formula 1, a mixture ofdiastereomers, or a pharmaceutically acceptable salt, solvate, orprodrug thereof, in a pharmaceutically acceptable vehicle, carrier,diluent, or excipient, or a combination thereof, for enteral,intravenous infusion, oral, parenteral, topical and/or ocularadministration.

In yet another embodiment of the invention, there are providedpharmaceutical compositions comprising at least one of the compounds ofFormula 1, a single enantiomer of a compound of Formula 1, a mixture ofthe (+)-enantiomer and the (−)-enantiomer, a mixture of about 90% ormore by weight of the (−)-enantiomer and about 10% or less by weight ofthe (+)-enantiomer, a mixture of about 90% or more by weight of the(+)-enantiomer and about 10% or less by weight of the (−)-enantiomer, anindividual diastereomer of a compound of Formula 1, a mixture ofdiastereomers, or a pharmaceutically acceptable salt, solvate, orprodrug thereof, in a pharmaceutically acceptable vehicle, carrier,diluent, or excipient, or a combination thereof, for the treatment ofconditions involving the inhibition of monoamine reuptake.

In another embodiment of the invention, there are provided methods ofmodulating monoamine reuptake, with one or more of the compounds orcompositions of Formula 1, a single enantiomer of a compound of Formula1, a mixture of the (+)-enantiomer and the (−)-enantiomer, a mixture ofabout 90% or more by weight of the (−)-enantiomer and about 10% or lessby weight of the (+)-enantiomer, a mixture of about 90% or more byweight of the (+)-enantiomer and about 10% or less by weight of the(−)-enantiomer, an individual diastereomer of a compound of Formula 1, amixture of diastereomers, or a pharmaceutically acceptable salt,solvate, or prodrug thereof.

In yet another embodiment of the invention, there are provided compoundsaccording to Formula 1 having one of the following structures:

or a single enantiomer, a mixture of the (+)-enantiomer and the(−)-enantiomer, a mixture of about 90% or more by weight of the(−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, amixture of about 90% or more by weight of the (+)-enantiomer and about10% or less by weight of the (−)-enantiomer, an individual diastereomer,a mixture of diastereomers, or a pharmaceutically acceptable salt,solvate, or prodrug thereof.

The present invention is intended to include all isotopes of all atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuterium(D) and tritium (T). Isotopes of carbon include ¹³C and ¹⁴C. Isotopes ofsulfur include ³²S, ³³S, ³⁴S, and ³⁶S. Isotopes of nitrogen include ¹⁴Nand ¹⁵N. Isotopes of oxygen include ¹⁶O, ¹⁷O, and ¹⁸O.

Isotopic hydrogen can be introduced into organic molecules by synthetictechniques that employ deuterated reagents whereby incorporation ratesare pre-determined and/or by exchange techniques wherein incorporationrates are determined by equilibrium conditions and may be highlyvariable depending on the reaction conditions. Synthetic techniques,where tritium or deuterium is directly and specifically inserted bytritiated or deuterated reagents of known isotopic content, may yieldhigh tritium or deuterium abundance, but can be limited by the chemistryrequired. In addition, the molecule being labeled may be changed,depending upon the severity of the synthetic reaction employed. Exchangetechniques, on the other hand, may yield lower tritium or deuteriumincorporation, often with the isotope being distributed over many siteson the molecule, but offer the advantage that they do not requireseparate synthetic steps and are less likely to disrupt the structure ofthe molecule being labeled.

In another aspect of the invention, there are provided methods oftreating a mammalian subject, particularly a human, suspected of having,or being prone to a disease or condition involving monoamine reuptake,comprising administering to a mammalian subject in need thereof atherapeutically effective amount of a compound of Formula 1, a singleenantiomer of a compound of Formula 1, a mixture of the (+)-enantiomerand the (−)-enantiomer, a mixture of about 90% or more by weight of the(−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, amixture of about 90% or more by weight of the (+)-enantiomer and about10% or less by weight of the (−)-enantiomer, an individual diastereomerof a compound of Formula 1, a mixture of diastereomers, or apharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments, the administering step in the above methodscomprises administering the compound of the invention in somecomposition, such as for example a single tablet, pill, capsule, asingle solution for intravenous injection, a single drinkable solution,a single dragee formulation or patch, and the like wherein the amountadministered is about 0.5 milligram to 400 milligram total daily dose.

In another aspect of the invention, there are provided methods fortreating a mammalian subject, particularly a human, suspected of having,or being prone to a disease or condition involving monoamine reuptake,comprising administering to a mammalian subject in need thereof atherapeutically effective amount of a monoamine reuptake inhibitorcomprising at least one of the compounds of Formula 1, a singleenantiomer of a compound of Formula 1, a mixture of the (+)-enantiomerand the (−)-enantiomer, a mixture of about 90% or more by weight of the(−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, amixture of about 90% or more by weight of the (+)-enantiomer and about10% or less by weight of the (−)-enantiomer, an individual diastereomerof a compound of Formula 1, a mixture of diastereomers, or apharmaceutically acceptable salt, solvate, or prodrug thereof, so as toaffect decreased inter-individual variation in plasma levels of saidcompound or a metabolite thereof during treatment of the above-mentioneddiseases as compared to the non-isotopically enriched compound.

In some embodiments, the inter-individual variation in plasma levels ofthe compounds of the invention, or metabolites thereof, is decreased bygreater than about 5%, as compared to the non-isotopically enrichedcompounds. In other embodiments, the inter-individual variation inplasma levels of the compounds of the invention, or metabolites thereof,is decreased by greater than about 10%, as compared to thenon-isotopically enriched compounds. In other embodiments, theinter-individual variation in plasma levels of the compounds of theinvention, or metabolites thereof, is decreased by greater than about20%, as compared to the non-isotopically enriched compounds. In otherembodiments, the inter-individual variation in plasma levels of thecompounds of the invention, or metabolites thereof, is decreased bygreater than about 30%, as compared to the non-isotopically enrichedcompounds. In other embodiments, the inter-individual variation inplasma levels of the compounds of the invention, or metabolites thereof,is decreased by greater than about 40%, as compared to thenon-isotopically enriched compounds. In other embodiments, theinter-individual variation in plasma levels of the compounds of theinvention, or metabolites thereof, is decreased by greater than about50%, as compared to the non-isotopically enriched compounds. Plasmalevels of the compounds of the invention, or metabolites thereof, aremeasured by the methods of Li et al Rapid Communications in MassSpectrometry 2005, 19(14), 1943-1950, which is hereby incorporated byreference in its entirety.

In another aspect of the invention, there are provided methods fortreating a mammalian subject, particularly a human, suspected of having,or being prone to a disease or condition involving monoamine reuptake,comprising administering to a mammalian subject in need thereof atherapeutically effective amount of a monoamine reuptake inhibitorcomprising at least one of the compounds of Formula 1, a singleenantiomer of a compound of Formula 1, a mixture of the (+)-enantiomerand the (−)-enantiomer, a mixture of about 90% or more by weight of the(−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, amixture of about 90% or more by weight of the (+)-enantiomer and about10% or less by weight of the (−)-enantiomer, an individual diastereomerof a compound of Formula 1, a mixture of diastereomers, or apharmaceutically acceptable salt, solvate, or prodrug thereof, so as toaffect increased average plasma levels of said compound or decreasedaverage plasma levels of at least one metabolite of said compound perdosage unit as compared to the non-isotopically enriched compound.

In some embodiments, the average plasma levels of the compounds of theinvention are increased by greater than about 5%, as compared to thenon-isotopically enriched compounds. In other embodiments, the averageplasma levels of the compounds of the invention are increased by greaterthan about 10%, as compared to the non-isotopically enriched compounds.In other embodiments, the average plasma levels of the compounds of theinvention are increased by greater than about 20%, as compared to thenon-isotopically enriched compounds. In other embodiments, the averageplasma levels of the compounds of the invention are increased by greaterthan about 30%, as compared to the non-isotopically enriched compounds.In other embodiments, the average plasma levels of the compounds of theinvention are increased by greater than about 40%, as compared to thenon-isotopically enriched compounds. In other embodiments, the averageplasma levels of the compounds of the invention are increased by greaterthan about 50%, as compared to the non-isotopically enriched compounds.

In some embodiments, the average plasma levels of a metabolite of thecompounds of the invention are decreased by greater than about 5%, ascompared to the non-isotopically enriched compounds. In otherembodiments, the average plasma levels of a metabolite of the compoundsof the invention are decreased by greater than about 10%, as compared tothe non-isotopically enriched compounds. In other embodiments, theaverage plasma levels of a metabolite of the compounds of the inventionare decreased by greater than about 20%, as compared to thenon-isotopically enriched compounds. In other embodiments, the averageplasma levels of a metabolite of the compounds of the invention aredecreased by greater than about 30%, as compared to the non-isotopicallyenriched compounds. In other embodiments, the average plasma levels of ametabolite of the compounds of the invention are decreased by greaterthan about 40%, as compared to the non-isotopically enriched compounds.In other embodiments, the average plasma levels of a metabolite of thecompounds of the invention are decreased by greater than about 50%, ascompared to the non-isotopically enriched compounds.

Plasma levels of the compounds of the invention, or metabolites thereof,are measured by the methods of Li et al Rapid Communications in MassSpectrometry 2005, 19(14), 1943-1950, which is hereby incorporated byreference in its entirety.

In another aspect of the invention, there are provided methods fortreating a mammalian subject, particularly a human, suspected of having,or being prone to a disease or condition involving monoamine reuptake,comprising administering to a mammalian subject in need thereof atherapeutically effective amount of a monoamine reuptake inhibitorcomprising a least one of the compounds of Formula 1, a singleenantiomer of a compound of Formula 1, a mixture of the (+)-enantiomerand the (−)-enantiomer, a mixture of about 90% or more by weight of the(−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, amixture of about 90% or more by weight of the (+)-enantiomer and about10% or less by weight of the (−)-enantiomer, an individual diastereomerof a compound of Formula 1, a mixture of diastereomers, or apharmaceutically acceptable salt, solvate, or prodrug thereof, so as toaffect a decreased inhibition of, and/or metabolism by at least onecytochrome P₄₅₀ isoform in mammalian subjects during treatment of theabove-mentioned diseases as compared to the non-isotopically enrichedcompound. Examples of cytochrome P₄₅₀ isoforms in mammalian subjectsinclude CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9,CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1,CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2,CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP1X1, CYP4Z1, CYP5A1, CYP7A1,CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21,CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51 and thelike.

In some embodiments, the decrease in inhibition of the cytochrome P₄₅₀isoform by compounds of the invention is greater than about 5%, ascompared to the non-isotopically enriched compounds. In otherembodiments, the decrease in inhibition of the cytochrome P₄₅₀ isoformby compounds of the invention is greater than about 10%, as compared tothe non-isotopically enriched compounds. In other embodiments, thedecrease in inhibition of the cytochrome P₄₅₀ isoform by compounds ofthe invention is greater than about 20%, as compared to thenon-isotopically enriched compounds. In other embodiments, the decreasein inhibition of the cytochrome P₄₅₀ isoform by compounds of theinvention is greater than about 30%, as compared to the non-isotopicallyenriched compounds. In other embodiments, the decrease in inhibition ofthe cytochrome P₄₅₀ isoform by compounds of the invention is greaterthan about 40%, as compared to the non-isotopically enriched compounds.In other embodiments, the decrease in inhibition of the cytochrome P₄₅₀isoform by compounds of the invention is greater than about 50%, ascompared to the non-isotopically enriched compounds.

The inhibition of the cytochrome P₄₅₀ isoform is measured by the methodsof Ko et al British Journal of Clinical Pharmacology 2000, 49(4),343-351, which is hereby incorporated by reference its entirety.

In another aspect of the invention, there are provided methods fortreating a mammalian subject, particularly a human, suspected of having,or being prone to a disease or condition involving monoamine reuptake,comprising administering to a mammalian subject in need thereof atherapeutically effective amount of a monoamine reuptake inhibitorcomprising a least one of the compounds of Formula 1, a singleenantiomer of a compound of Formula 1, a mixture of the (+)-enantiomerand the (−)-enantiomer, a mixture of about 90% or more by weight of the(−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, amixture of about 90% or more by weight of the (+)-enantiomer and about10% or less by weight of the (−)-enantiomer, an individual diastereomerof a compound of Formula 1, a mixture of diastereomers, or apharmaceutically acceptable salt, solvate, or prodrug thereof, so as toaffect a decreased metabolism via at least one polymorphically-expressedcytochrome P₄₅₀ isoform in mammalian subjects during treatment of theabove-mentioned diseases as compared to the non-isotopically enrichedcompound. Examples of polymorphically-expressed cytochrome P₄₅₀ isoformsin mammalian subjects include CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

In some embodiments, the decrease in metabolism of compounds of theinvention by the cytochrome P450 isoform is greater than about 5%, ascompared to the non-isotopically enriched compound. In otherembodiments, the decrease in metabolism of compounds of the invention bythe cytochrome P₄₅₀ isoform is greater than about 10%, as compared tothe non-isotopically enriched compound. In other embodiments, thedecrease in metabolism of compounds of the invention by the cytochromeP₄₅₀ isoform is greater than about 20%, as compared to thenon-isotopically enriched compound. In other embodiments, the decreasein metabolism of compounds of the invention by the cytochrome P₄₅₀isoform is greater than about 30%, as compared to the non-isotopicallyenriched compound. In other embodiments, the decrease in metabolism ofcompounds of the invention by the cytochrome P₄₅₀ isoform is greaterthan about 40%, as compared to the non-isotopically enriched compound.In other embodiments, the decrease in metabolism of compounds of theinvention by the cytochrome P₄₅₀ isoform is greater than about 50%, ascompared to the non-isotopically enriched compound.

The metabolic activity of the cytochrome P₄₅₀ isoform is measured by themethod described in Example 14 below.

In another embodiment of the invention, there are provided methods fortreating a mammalian subject, particularly a human, suspected of having,or being prone to a disease or condition involving monoamine reuptake,comprising administering to a mammalian subject in need thereof atherapeutically effective amount of a monoamine reuptake inhibitorcomprising at least one of the compounds of Formula 1, a singleenantiomer of a compound of Formula 1, a mixture of the (+)-enantiomerand the (−)-enantiomer, a mixture of about 90% or more by weight of the(−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, amixture of about 90% or more by weight of the (+)-enantiomer and about10% or less by weight of the (−)-enantiomer, an individual diastereomerof a compound of Formula 1, a mixture of diastereomers, or apharmaceutically acceptable salt, solvate, or prodrug thereof, so as toaffect improved biogenic monoamine levels as compared to thenon-isotopically enriched compound.

In some embodiments, biogenic monoamine levels are increased by greaterthan about 5%. In other embodiments, biogenic monoamine levels areincreased by greater than about 10%. In other embodiments, biogenicmonoamine levels are increased by greater than about 20%. In otherembodiments, biogenic monoamine levels are increased by greater thanabout 30%. In other embodiments, biogenic monoamine levels are increasedby greater than about 40%. In other embodiments, biogenic monoaminelevels are increased by greater than about 50%.

Biogenic monoamine levels are measured by the methods of Li et al RapidCommunications in Mass Spectrometry 2005, 19(14), 1943-1950, which ishereby incorporated by reference in its entirety.

In another aspect of the invention, there are provided methods fortreating a mammalian subject, particularly a human, suspected of having,or being prone to a disease or condition involving monoamine reuptake,comprising administering to a mammalian subject in need thereof atherapeutically effective amount of a monoamine reuptake inhibitorcomprising at least one of the compounds of Formula 1, a singleenantiomer of a compound of Formula 1, a mixture of the (+)-enantiomerand the (−)-enantiomer, a mixture of about 90% or more by weight of the(−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, amixture of about 90% or more by weight of the (+)-enantiomer and about10% or less by weight of the (−)-enantiomer, an individual diastereomerof a compound of Formula 1, a mixture of diastereomers, or apharmaceutically acceptable salt, solvate, or prodrug thereof, so as toaffect an improved clinical effect as compared to the non-isotopicallyenriched compound. Examples of improved clinical effects include but arenot limited to accelerated rate of healing, accelerated rate of symptomrelief, improved patient compliance, and/or reduced substance abusewithdrawal symptomology during the treatment.

In another aspect of the invention, there are provided methods fortreating a mammalian subject, particularly a human, suspected of having,or being prone to a disease or condition involving monoamine reuptake,comprising administering to a mammalian subject in need thereof atherapeutically effective amount of a monoamine reuptake inhibitorcomprising at least one of the compounds of Formula 1, a singleenantiomer of a compound of Formula 1, a mixture of the (+)-enantiomerand the (−)-enantiomer, a mixture of about 90% or more by weight of the(−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, amixture of about 90% or more by weight of the (+)-enantiomer and about10% or less by weight of the (−)-enantiomer, an individual diastereomerof a compound of Formula 1, a mixture of diastereomers, or apharmaceutically acceptable salt, solvate, or prodrug thereof, providedthat said compound of Formula 1 contains at least one deuterium atom,and provided that deuterium enrichment in said compound of Formula 1 isat least about 1%.

In some embodiments, disease or condition involving monoamine reuptakeis selected from the group consisting of anxiety disorder, generalizedanxiety disorder, depression, post-traumatic stress disorder,obsessive-compulsive disorder, panic disorder, hot flashes, seniledementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptivepain, neuropathic pain, painful diabetic retinopathy, bipolardepression, obstructive sleep apnea, psychiatric disorders, premenstrualdysphoric disorder, social phobia, social anxiety disorder, urinaryincontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury,calcium overload in brain cells, drug dependence, and prematureejaculation.

In another aspect of the invention, there are provided oral multipleunit tablet pharmaceutical compositions comprising a first component anda second component for the treatment of a drug addiction. In someembodiments, the first component comprises at least one of the compoundsof Formula 1, a single enantiomer of a compound of Formula 1, a mixtureof the (+)-enantiomer and the (−)-enantiomer, a mixture of about 90% ormore by weight of the (−)-enantiomer and about 10% or less by weight ofthe (+)-enantiomer, a mixture of about 90% or more by weight of the(+)-enantiomer and about 10% or less by weight of the (−)-enantiomer, anindividual diastereomer of a compound of Formula 1, a mixture ofdiastereomers, or a pharmaceutically acceptable salt, solvate, orprodrug thereof. In certain embodiments, the second component comprisesone or more opioid antagonists. In some of these embodiments, the opioidantagonist is selected from the group consisting of nalmefene, naloxone,and naltrexone, and the like. In further embodiments, the drug addictionis selected from the group consisting of addiction to tobacco, alcohol,marijuana, and cocaine. In certain embodiments, the first component isseparated from the second component by a coating layer covering thefirst and the second components. Such coating agents are known to thoseskilled in the art.

In another aspect of the invention, there are provided methods oftreating a mammal for a drug addiction comprising administering to themammal a composition comprising a first component and a secondcomponent, where the first component comprises of at least one of thecompounds of Formula 1, a single enantiomer of a compound of Formula 1,a mixture of the (+)-enantiomer and the (−)-enantiomer, a mixture ofabout 90% or more by weight of the (−)-enantiomer and about 10% or lessby weight of the (+)-enantiomer, a mixture of about 90% or more byweight of the (+)-enantiomer and about 10% or less by weight of the(−)-enantiomer, an individual diastereomer of a compound of Formula 1, amixture of diastereomers, or a pharmaceutically acceptable salt,solvate, or prodrug thereof, and the second component comprises one ormore opioid antagonists. In some of these embodiments, the opioidantagonist is selected from the group consisting of nalmefene, naloxone,and naltrexone, and the like. In further embodiments, the drug addictionis selected from the group consisting of addiction to tobacco, alcohol,marijuana, and cocaine. In still further embodiments, the firstcomponent can elicit an improved clinical effect for the treatment of adrug addiction, as compared to the non-isotopically enriched analog ofthe first component (e.g., accelerated rate of healing, accelerated rateof symptom relief, improved patient compliance, and/or reduced substanceabuse withdrawal symptomatology during the treatment).

In some embodiments, the administering step comprises administering thefirst component and the second component nearly simultaneously. Theseembodiments include those in which the two compounds are in the sameadministrable composition, i.e., a single tablet, pill, or capsule, or asingle solution for intravenous injection, or a single drinkablesolution, or a single dragee formulation or patch, contains bothcompounds. The embodiments also include those in which each compound isin a separate administrable composition, but the patient is directed totake the separate compositions nearly simultaneously, i.e., one pill istaken right after the other or that one injection of one compound ismade right after the injection of another compound, etc. In someembodiments, a patient is infused with an intravenous formulation of onecompound prior to the infusion of an intravenous formulation of theother compound. In these embodiments, the infusion may take some time,such as a few minutes, a half hour, or an hour, or longer. If the twointravenous infusions are done one right after the other, suchadministration is considered to be nearly simultaneously within thescope of the present disclosure, even though there was a lapse of sometime between the start of one infusion and the start of the nextinfusion.

In other embodiments the administering step comprises administering oneof the first component and the second component and then administeringthe other one of the first component and the second component. In theseembodiments, the patient may be administered a composition comprisingone of the compounds and then at some time, a few minutes or a fewhours, later be administered another composition comprising the otherone of the compounds. Also included in these embodiments are those inwhich the patient is administered a composition comprising one of thecompounds on a routine or continuous basis while receiving a compositioncomprising the other compound occasionally. In further embodiments, thepatient may receive both compounds on a routine or continuous basis,such as continuous infusion of the compound through an IV line.

In still another aspect of the invention, there are providedeffervescent dosage forms comprising a first component and a secondcomponent, wherein the first component is one or more effervescentexcipients, and the second component is at least one of the compounds ofFormula 1, a single enantiomer of a compound of Formula 1, a mixture ofthe (+)-enantiomer and the (−)-enantiomer, a mixture of about 90% ormore by weight of the (−)-enantiomer and about 10% or less by weight ofthe (+)-enantiomer, a mixture of about 90% or more by weight of the(+)-enantiomer and about 10% or less by weight of the (−)-enantiomer, anindividual diastereomer of a compound of Formula 1, a mixture ofdiastereomers, or a pharmaceutically acceptable salt, solvate, orprodrug thereof, and optionally one or more pharmaceutically acceptableexcipients.

In another aspect of the invention, there are provided extended releasepharmaceutical dosage forms comprising at least one of the compounds ofFormula 1, a single enantiomer of a compound of Formula 1, a mixture ofthe (+)-enantiomer and the (−)-enantiomer, a mixture of about 90% ormore by weight of the (−)-enantiomer and about 10% or less by weight ofthe (+)-enantiomer, a mixture of about 90% or more by weight of the(+)-enantiomer and about 10% or less by weight of the (−)-enantiomer, anindividual diastereomer of a compound of Formula 1, a mixture ofdiastereomers, or a pharmaceutically acceptable salt, solvate, orprodrug thereof, a hydrophilic or hydrophobic matrix, a water-solubleseparating layer, an enteric coating layer, and optionally one or morepharmaceutically acceptable excipients.

In still another aspect of the invention, there are provided entericcoated pharmaceutical dosage forms comprising at least one of thecompounds of Formula 1, a single enantiomer of a compound of Formula 1,a mixture of the (+)-enantiomer and the (−)-enantiomer, a mixture ofabout 90% or more by weight of the (−)-enantiomer and about 10% or lessby weight of the (+)-enantiomer, a mixture of about 90% or more byweight of the (+)-enantiomer and about 10% or less by weight of the(−)-enantiomer, an individual diastereomer of a compound of Formula 1, amixture of diastereomers, or a pharmaceutically acceptable salt,solvate, or prodrug thereof, a disruptable semi-permeable membrane andone or more swellable substances, wherein the dosage form has an instantinhibitor-releasing part and at least one delayed inhibitor-releasingpart, and is capable of giving a discontinuous release of the compoundin the form of at least two consecutive pulses separated in time from0.1 up to 24 hours.

In still another aspect of the invention, there are provided stablepharmaceutical dosage forms for oral administration to mammaliansubjects which comprises at least one of the compounds of Formula 1, asingle enantiomer of a compound of Formula 1, a mixture of the(+)-enantiomer and the (−)-enantiomer, a mixture of about 90% or more byweight of the (−)-enantiomer and about 10% or less by weight of the(+)-enantiomer, a mixture of about 90% or more by weight of the(+)-enantiomer and about 10% or less by weight of the (−)-enantiomer, anindividual diastereomer of a compound of Formula 1, a mixture ofdiastereomers, or a pharmaceutically acceptable salt, solvate, orprodrug thereof, and optionally one or more pharmaceutical adjuvants,enclosed in an intermediate reactive layer comprising a gastricjuice-resistant polymeric layered material partially neutralized withalkali and having cation exchange capacity and a gastric juice-resistantouter layer.

Unless otherwise indicated, when a substituent is deemed to be“optionally substituted,” it is meant that the substituent is a groupthat may be substituted with one or more group(s) individually andindependently selected from the group consisting of hydrogen, deuterium,alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, hydroxy, alkoxy,aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, silyl,trihalomethanesulfonyl, and amino, including mono- and di-substitutedamino groups, and the protected derivatives thereof. The protectinggroups that may form the protective derivatives of the abovesubstituents are known to those of skill in the art examples of whichmay be found in references such as Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999,which is incorporated by reference herein in its entirety.

The compounds according to this invention may occur as any reasonabletautomer as recognized by one skilled in the art or a mixture of suchtautomers. The term “tautomer” or “tautomerism” refers to one of two ormore structural isomers that exist in equilibrium and are readilyconverted from one isomeric form to another. Examples include keto-enoltautomers, such as acetone/propen-2-ol and the like, ring-chaintautomers, such as glucose/2,3,4,5,6-pentahydroxy-hexanal and the like.The compounds described herein may have one or more tautomers andtherefore include various isomers. All such isomeric forms of thesecompounds are expressly included in the present invention.

The compounds according to this invention may contain one or moreasymmetric atoms and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures or individual diastereomers.The term “stereoisomer” refers to a chemical compound having the samemolecular weight, chemical composition, and constitution as another, butwith the atoms grouped differently. That is, certain identical chemicalmoieties are at different orientations in space and, therefore, whenpure, have the ability to rotate the plane of polarized light. However,some pure stereoisomers may have an optical rotation that is so slightthat it is undetectable with present instrumentation. The compoundsdescribed herein may have one or more asymmetrical atoms and thereforeinclude various stereoisomers. All such isomeric forms of thesecompounds are expressly included in the present invention.

Each stereogenic carbon or sulfur may be of R or S configuration.Although the specific compounds exemplified in this application may bedepicted in a particular configuration, compounds having the oppositestereochemistry at any given chiral center or mixtures thereof are alsoenvisioned. When chiral centers are found in the derivatives of thisinvention, it is to be understood that this invention encompasses allpossible stereoisomers.

The terms “optically pure compound” or “optically pure isomer” refers toa single stereoisomer of a chiral compound regardless of theconfiguration of the said compound.

The term “substantially homogeneous” refers to collections of moleculeswherein at least about 80%, preferably at least about 90% and morepreferably at least about 95% of the molecules are a single compound ora single stereoisomer thereof, or to collections of molecules wherein atleast about 80%, preferably at least about 90% and more preferably atleast about 95% of the molecules are fully substituted (e.g.,deuterated) at the positions stated.

As used herein, the term “attached” signifies a stable covalent bond,certain preferred points of attachment being apparent to those skilledin the art.

The terms “optional” or “optionally” refer to occurrence ornon-occurrence of the subsequently described event or circumstance, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not. In such context, the sentence“optionally substituted alkyl group” means that the alkyl group may ormay not be substituted and the description includes both a substitutedand an unsubstituted alkyl group.

The term “effective amount” of a compound refers a sufficient amount ofthe compound that provides a desired effect but with no- oracceptable-toxicity. This amount may vary from subject to subject,depending on the species, age, and physical condition of the subject,the severity of the disease that is being treated, the particularcompound used, its mode of administration, and the like. A suitableeffective amount may be determined by one of ordinary skill in the art.

The term “pharmaceutically acceptable” refers to a compound, additive orcomposition that is not biologically or otherwise undesirable. Forexample, the additive or composition may be administered to a subjectalong with a compound of the invention without causing any undesirablebiological effects or interacting in an undesirable manner with any ofthe other components of the pharmaceutical composition in which it iscontained.

The term “pharmaceutically acceptable salts” includes hydrochloric salt,hydrobromic salt, hydroiodic salt, hydrofluoric salt, sulfuric salt,citric salt, maleic salt, acetic salt, lactic salt, nicotinic salt,succinic salt, oxalic salt, phosphoric salt, malonic salt, salicylicsalt, phenylacetic salt, stearic salt, pyridine salt, ammonium salt,piperazine salt, diethylamine salt, nicotinamide salt, formic salt, ureasalt, sodium salt, potassium salt, calcium salt, magnesium salt, zincsalt, lithium salt, cinnamic salt, methylamino salt, methanesulfonicsalt, picric salt, tartaric salt, triethylamino salt, dimethylaminosalt, tris(hydroxymethyl)aminomethane salt and the like. Additionalpharmaceutically acceptable salts are known to those of skill in theart.

When used in conjunction with a compound of this invention, the terms“elicit”, “eliciting,” “modulator”, “modulate”, “modulating”,“regulator”, “regulate” or “regulating” the activity refer to a compoundthat can act as an agonist, an inverse agonist, an inhibitor, or anantagonist of a particular enzyme or receptor, such as for example aserotonin receptor.

The terms “drug”, “therapeutic agent” and “chemotherapeutic agent”,refer to a compound or compounds and pharmaceutically acceptablecompositions thereof that are administered to mammalian subjects asprophylactic or remedy in the treatment of a disease or medicalcondition. Such compounds may be administered to the subject via oralformulation, inhalation, intravenous infusion, ocular application,transdermal formulation or by injection.

The term “subject” refers to an animal, preferably a mammal, and mostpreferably a human, who is the object of treatment, observation orexperiment. The mammal may be selected from the group consisting ofmice, rats, hamsters, gerbils, rabbits, guinea pigs, dogs, cats, sheep,goats, cows, horses, giraffes, platypuses, primates, such as monkeys,chimpanzees, and apes, and humans.

The term “therapeutically effective amount” is used to indicate anamount of an active compound, or pharmaceutical agent, that elicits thebiological or medicinal response indicated. This response may occur in atissue, system (animal including human) that is being sought by aresearcher, veterinarian, medical doctor or other clinician.

The terms “treating,” “treatment,” “therapeutic,” or “therapy” do notnecessarily mean total loss of nociception. Any alleviation of anyundesired signs or symptoms of a disease, such as those involvingmonoamine reuptake, anxiety disorder, generalized anxiety disorder,depression, post-traumatic stress disorder, obsessive-compulsivedisorder, panic disorder, hot flashes, senile dementia, migraine,hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathicpain, painful diabetic retinopathy, bipolar depression, obstructivesleep apnea, psychiatric disorders, premenstrual dysphoric disorder,social phobia, social anxiety disorder, urinary incontinence, anorexia,bulimia nervosa, obesity, ischemia, head injury, calcium overload inbrain cells, drug dependence, and/or premature ejaculation, or a subsetof these conditions, to any extent can be considered treatment ortherapy. Furthermore, treatment may include acts that may worsen thepatient's overall feeling of well-being or appearance.

The term “Lewis acid” refers to a molecule that can accept an unsharedpair of electrons and as such would be obvious to one of ordinary skilland knowledge in the art. The definition of “Lewis acid” includes but isnot limited to: boron trifluoride, boron trifluoride etherate, borontrifluoride tetrahydrofuran complex, boron trifluoride tert-butyl-methylether complex, boron trifluoride dibutyl ether complex, borontrifluoride dihydrate, boron trifluoride di-acetic acid complex, borontrifluoride dimethyl sulfide complex, boron trichloride, borontrichloride dimethyl sulfide complex, boron tribromide, boron tribromidedimethyl sulfide complex, boron triiodide, triimethoxyborane,triethoxyborane, trimethylaluminum, triethylaluminum, aluminumtrichloride, aluminum trichloride tetrahydrofuran complex, aluminumtribromide, titanium tetrachloride, titanium tetrabromide, titaniumiodide, titanium tetraethoxide, titanium tetraisopropoxide, scandium(III) trifluoromethanesulfonate, yttrium (III)trifluoromethanesulfonate, ytterbium (III) trifluoromethanesulfonate,lanthanum (III) trifluoromethanesulfonate, zinc (II) chloride, zinc (II)bromide, zinc (II) iodide, zinc (II) trifluoromethanesulfonate, zinc(II) sulfate, magnesium sulfate, Lithium perchlorate, copper (II)trifluoromethanesulfonate, copper (II) tetrafluoroborate and the like.Certain Lewis acids may have optically pure ligands attached to theelectron acceptor atom, as set forth in Corey, E. J. Angewandte Chemie,International Edition (2002), 41(10), 1650-1667; Aspinall, H. C.Chemical Reviews (Washington, D.C., United States) (2002), 102(6),1807-1850; Groger, H. Chemistry—A European Journal (2001), 7(24),5246-5251; Davies, H. M. L. Chemtracts (2001), 14(11), 642-645; Wan, Y.Chemtracts (2001), 14(11), 610-615; Kim, Y. H. Accounts of ChemicalResearch (2001), 34(12), 955-962; Seebach, D. Angewandte Chemie,International Edition (2001), 40(1), 92-138; Blaser, H. U. AppliedCatalysis, A: General (2001), 221(1-2), 119-143; Yet, L. AngewandteChemie, International Edition (2001), 40(5), 875-877; Jorgensen, K. A.Angewandte Chemie, International Edition (2000), 39(20), 3558-3588;Dias, L. C. Current Organic Chemistry (2000), 4(3), 305-342; Spindler,F. Enantiomer (1999), 4(6), 557-568; Fodor, K. Enantiomer (1999), 4(6),497-511; Shimizu, K. D.; Comprehensive Asymmetric Catalysis I-III(1999), 3, 1389-1399; Kagan, H. B. Comprehensive Asymmetric CatalysisI-III (1999), 1, 9-30; Mikami, K. Lewis Acid Reagents (1999), 93-136 andall references cited therein. Such Lewis acids may be used by one ofordinary skill and knowledge in the art to produce optically purecompounds from achiral starting materials.

The term “acylating agent” refers to a molecule that can transfer analkylcarbonyl, substituted alkylcarbonyl or aryl carbonyl group toanother molecule. The definition of “acylating agent” includes but isnot limited to ethyl acetate, vinyl acetate, vinyl propionate, vinylbutyrate, isopropenyl acetate, 1-ethoxyvinyl acetate, trichloroethylbutyrate, trifluoroethyl butyrate, trifluoroethyl laureate, S-ethylthiooctanoate, biacetyl monooxime acetate, acetic anhydride, acetylchloride, succinic anhydride, diketene, diallyl carbonate, carbonic acidbut-3-enyl ester cyanomethyl ester, amino acid and the like.

The term “nucleophile” or “nucleophilic reagent” refers to a negativelycharged or neutral molecule that has an unshared pair of electrons andas such would be obvious to one of ordinary skill and knowledge in theart. The definition of “nucleophile” includes but is not limited to:water, alkylhydroxy, alkoxy anion, arylhydroxy, aryloxy anion,alkylthiol, alkylthio anion, arylthiol, arylthio anion, ammonia,alkylamine, arylamine, alkylamine anion, arylamine anion, hydrazine,alkyl hydrazine, arylhydrazine, alkylcarbonyl hydrazine, arylcarbonylhydrazine, hydrazine anion, alkyl hydrazine anion, arylhydrazine anion,alkylcarbonyl hydrazine anion, arylcarbonyl hydrazine anion, cyanide,azide, hydride, alkyl anion, aryl anion and the like.

The term “electrophile” or “electrophilic reagent” refers to apositively charged or neutral molecule that has an open valence shell oran attraction for an electron-rich reactant and as such would be obviousto one of ordinary skill and knowledge in the art. The definition of“electrophile” includes but is not limited to: hydronium, acylium, Lewisacids, such as for example, boron trifluoride and the like, halogens,such as for example Br₂ and the like, carbocations, such as for exampletert-butyl cation and the like, diazomethane,trimethylsilyldiazomethane, alkyl halides, such as for example methyliodide, trideuteromethyl iodide (CD₃I), benzyl bromide and the like,alkyl triflates, such as for example methyl triflate and the like, alkylsulfonates, such as for example ethyl toluenesulfonate, butylmethanesulfonate, dimethylsulfate, hexadeuterodimethylsulfate((CD₃)₂SO₄) and the like, acyl halides, such as for example acetylchloride, benzoyl bromide and the like, acid anhydrides, such as forexample acetic anhydride, succinic anhydride, maleic anhydride and thelike, isocyanates, such as for example methyl isocyanate,phenylisocyanate and the like, chloroformates, such as for examplemethyl chloroformate, ethyl chloroformate, benzyl chloroformate and thelike, sulfonyl halides, such as for example methanesulfonyl chloride,p-toluenesulfonyl chloride and the like, silyl halides, such as forexample trimethylsilyl chloride, tert-butyldimethylsilyl chloride andthe like, phosphoryl halide such as for example dimethyl chlorophosphateand the like, alpha-beta-unsaturated carbonyl compounds such as forexample acrolein, methyl vinyl ketone, cinnamaldehyde and the like.

The term “leaving group” (LG) refers to any atom (or group of atoms)that is stable in its anion or neutral form after it has been displacedby a nucleophile and as such would be obvious to one of ordinary skilland knowledge in the art. The definition of “leaving group” includes butis not limited to: water, methanol, ethanol, chloride, bromide, iodide,methanesulfonate, tolylsulfonate, trifluoromethanesulfonate, acetate,trichloroacetate, benzoate and the like.

The term “oxidant” refers to any reagent that will increase theoxidation state of an atom, such as for example, hydrogen, carbon,nitrogen, sulfur, phosphorus and the like in the starting material byeither adding an oxygen to this atom or removing an electron from thisatom and as such would be obvious to one of ordinary skill and knowledgein the art. The definition of “oxidant” includes but is not limited to:osmium tetroxide, ruthenium tetroxide, ruthenium trichloride, potassiumpermanganate, meta-chloroperbenzoic acid, hydrogen peroxide, dimethyldioxirane and the like.

The term “metal ligand” refers to a molecule that has an unshared pairof electrons and can coordinate to a metal atom and as such would beobvious to one of ordinary skill and knowledge in the art. Thedefinition of “metal ligand” includes but is not limited to: water,alkoxy anion, alkylthio anion, ammonia, trialkylamine, triarylamine,trialkylphosphine, triarylphosphine, cyanide, azide and the like.

The term “reducing reagent” refers to any reagent that will decrease theoxidation state of an atom in the starting material by either adding ahydrogen to this atom, or adding an electron to this atom, or byremoving an oxygen from this atom and as such would be obvious to one ofordinary skill and knowledge in the art. The definition of “reducingreagent” includes but is not limited to: borane-dimethyl sulfidecomplex, 9-borabicyclo[3.3.1.]nonane (9-BBN), catechol borane, lithiumborohydride, lithium borodeuteride, sodium borohydride, sodiumborodeuteride, sodium borohydride-methanol complex, potassiumborohydride, sodium hydroxyborohydride, lithium triethylborohydride,lithium n-butylborohydride, sodium cyanoborohydride, sodiumcyanoborodeuteride, calcium (II) borohydride, lithium aluminum hydride,lithium aluminum deuteride, diisobutylAluminum hydride,n-butyl-diisobutylaluminum hydride, Sodium bis-methoxyethoxyAluminumhydride, triethoxysilane, diethoxymethylsilane, lithium hydride,lithium, sodium, hydrogen Ni/B, and the like. Certain acidic and Lewisacidic reagents enhance the activity of reducing reagents. Examples ofsuch acidic reagents include: acetic acid, methanesulfonic acid,hydrochloric acid, and the like. Examples of such Lewis acidic reagentsinclude: trimethoxyborane, triethoxyborane, aluminum trichloride,lithium chloride, vanadium trichloride, dicyclopentadienyl titaniumdichloride, cesium fluoride, potassium fluoride, zinc (II) chloride,zinc (II) bromide, zinc (II) iodide, and the like.

The term “coupling reagent” refers to any reagent that will activate thecarbonyl of a carboxylic acid and facilitate the formation of an esteror amide bond. The definition of “coupling reagent” includes but is notlimited to: acetyl chloride, ethyl chloroformate,dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),N-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu),4-nitrophenol, pentafluorophenol,2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU), O-benzotriazole-N,N,N′N′-tetramethyluronium hexafluorophosphate(HBTU), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP),benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate,bromo-trispyrrolidino-phosphonium hexafluorophosphate,2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TNTU), O-(N-succinimidyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TSTU), tetramethylfluoroformamidiniumhexafluorophosphate and the like.

The term “removable protecting group” or “protecting group” refers toany group which when bound to a functionality, such as the oxygen atomof a hydroxyl or carboxyl group or the nitrogen atom of an amino group,prevents reactions from occurring at these functional groups and whichprotecting group can be removed by conventional chemical or enzymaticsteps to reestablish the functional group. The particular removableprotecting group employed is not critical.

The definition of “hydroxyl protecting group” includes but is notlimited to:

a) Methyl, tert-butyl, allyl, propargyl, p-chlorophenyl,p-methoxyphenyl, p-nitrophenyl, 2,4-dinitrophenyl,2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl, methoxymethyl,methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,p-methoxy-benzyloxymethyl, p-nitrobenzyloxymethyl,o-nitrobenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl,tert-butoxymethyl, 4-pentenyloxymethyl, tert-butyldimethylsiloxymethyl,thexyldimethylsiloxymethyl, tert-butyldiphenylsiloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,menthoxymethyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl,1-[2-(trimethylsilyl)ethoxy]ethyl, 1-methyl-1-ethoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,1-methyl-1-phenoxyethyl, 2,2,2-trichloroethyl,1-dianisyl-2,2,2-trichloroethyl,1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 2-trimethylsilylethyl,2-(benzylthio)ethyl, 2-(phenylselenyl)ethyl, tetrahydropyranyl,3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl,4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl,4-methoxytetrahydropyranyl S,S-dioxide,1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl,tetrahydrofuranyl, tetrahydrothiofuranyl and the like;

b) Benzyl, 2-nitrobenzyl, 2-trifluoromethylbenzyl, 4-methoxybenzyl,4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl,4-phenylbenzyl, 4-acylaminobenzyl, 4-azidobenzyl,4-(methylsulfinyl)benzyl, 2,4-dimethoxybenzyl, 4-azido-3-chlorobenzyl,3,4-dimethoxybenzyl, 2,6-dichlorobenzyl, 2,6-difluorobenzyl,1-pyrenylmethyl, diphenylmethyl, 4,4′-dinitrobenzhydryl, 5-benzosuberyl,triphenylmethyl (trityl), α-naphthyldiphenylmethyl,(4-methoxyphenyl)-diphenyl-methyl, di-(p-methoxyphenyl)-phenylmethyl,tri-(p-methoxyphenyl)methyl,4-(4′-bromophenacyloxy)-phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′-dimethoxy-3″-[N-(imidazolylmethyl)]trityl,4,4′-dimethoxy-3″-[N-(imidazolylethyl)carbamoyl]trityl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl,4-(17-tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4′-dimethoxytrityl,9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl and thelike;

c) Trimethylsilyl, triethylsilyl, triisopropylsilyl,dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl,tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl,(2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl,tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl and the like;

d) —C(O)R₃₀, where R₃₀ is selected from the group consisting of alkyl,substituted alkyl, aryl and more specifically R₃₀=hydrogen, methyl,ethyl, tert-butyl, adamantyl, crotyl, chloromethyl, dichloromethyl,trichloromethyl, trifluoromethyl, methoxymethyl, triphenylmethoxymethyl,phenoxymethyl, 4-chlorophenoxymethyl, phenylmethyl, diphenylmethyl,4-methoxycrotyl, 3-phenylpropyl, 4-pentenyl, 4-oxopentyl,4,4-(ethylenedithio)pentyl,5-[3-bis(4-methoxyphenyl)hydroxymethylphenoxy]-4-oxopentyl, phenyl,4-methylphenyl, 4-nitrophenyl, 4-fluorophenyl, 4-chlorophenyl,4-methoxyphenyl, 4-phenylphenyl, 2,4,6-trimethylphenyl, α-naphthyl,benzoyl and the like;

e) —C(O)OR₃₀, where R₃₀ is selected from the group consisting of alkyl,substituted alkyl, aryl and more specifically R₃₀=methyl, methoxymethyl,9-fluorenylmethyl, ethyl, 2,2,2-trichloromethyl,1,1-dimethyl-2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenylsulfonyl)ethyl, isobutyl, tert-butyl, vinyl, allyl,4-nitrophenyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-methoxybenzyl,2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2-(methylthiomethoxy)ethyl,2-dansenylethyl, 2-(4-nitrophenyl)ethyl, 2-(2,4-dinitrophenyl)ethyl,2-cyano-1-phenylethyl, thiobenzyl, 4-ethoxy-1-naphthyl and the like.Other examples of hydroxyl protecting groups are given in Greene andWutts, above.

The definition of “amino protecting group” includes but is not limitedto:

2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl,2-phosphonioethyl, 1-methyl-1-(triphenylphosphonio)ethyl,1,1-dimethyl-2-cyanoethyl, 2-dansylethyl, 2-(4-nitrophenyl)ethyl,4-phenylacetoxybenzyl, 4-azidobenzyl, 4-azidomethoxybenzyl,m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl,m-nitrophenyl, 3,5-dimethoxybenzyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl, o-nitrobenzyl,α-methylnitropiperonyl, 3,4-dimethoxy-6-nitrobenzyl, N-benzenesulfenyl,N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl,N-pentachlorobenzenesulfenyl. N-2-nitro-4-methoxybenzenesulfenyl,N-triphenylmethylsulfenyl,N-1-(2,2,2-trifluoro-1,1-diphenyl)ethylsulfenyl,N-3-nitro-2-pyridinesulfenyl, N-p-toluenesulfonyl, N-benzenesulfonyl,N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,N-2,4,6-trimethoxybenzene-sulfonyl,N-2,6-dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl,N-2,3,5,6-tetramethyl-4-methoxybenzenesulfonyl and the like;

—C(O)OR₃₀, where R₃₀ is selected from the group consisting of alkyl,substituted alkyl, aryl and more specifically R₃₀=methyl, ethyl,9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl.9-(2,7-dibromo)fluorenylmethyl, 17-tetrabenzo[a,c,g,i]fluorenylmethyl.2-chloro-3-indenylmethyl, benz[f]inden-3-ylmethyl,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothloxanthyl)]methyl,1,1-dioxobenzo[b]thiophene-2-ylmethyl, 2,2,2-trichloroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,2-chloroethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-tert-butylphenyl)-1-methylethyl, 2-(2′-pyridyl)ethyl,2-(4′-pyridyl)ethyl, 2,2-bis(4′-nitrophenyl)ethyl,N-(2-pivaloylamino)-1,1-dimethylethyl,2-[(2-nitrophenyl)dithio]-1-phenylethyl, tert-butyl, 1-adamantyl,2-adamantyl, Vinyl, allyl, 1-Isopropylallyl, cinnamyl 4-nitrocinnamyl,3-(3-pyridyl)prop-2-enyl, 8-quinolyl, N-Hydroxypiperidinyl, alkyldithio,benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl. p-chlorobenzyl,2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl,diphenylmethyl, tert-amyl, S-benzyl thiocarbamate, butynyl,p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl,p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl,o-(N,N′-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N′-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-Iodoethyl, isobornyl, isobutyl,isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-4′-pyridylethyl, phenyl, p-(phenylazo)benzyl,2,4,6-trimethylphenyl, 4-(trimethylammonium)benzyl,2,4,6-trimethylbenzyl and the like. Other examples of amino protectinggroups are given in Greene and Wutts, above.

The definition of “carboxyl protecting group” includes but is notlimited to:

2-N-(morpholino)ethyl, choline, methyl, methoxyethyl, 9-fluorenylmethyl,methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,pivaloyloxymethyl, phenylacetoxymethyl, triisopropylsilylmethyl,cyanomethyl, acetol, p-bromophenacyl. α-methylphenacyl,p-methoxyphenacyl, desyl, carboxamidomethyl,p-azobenzenecarboxamido-methyl, N-phthalimidomethyl,(methoxyethoxy)ethyl, 2,2,2-trichloroethyl, 2-fluoroethyl,2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 4-chlorobutyl, 5-chloropentyl,2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl,2-(2-pyridyl)ethyl, 2-(p-methoxyphenyl)ethyl,2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl,2-(4-acetyl-2-nitrophenyl)ethyl, 2-cyanoethyl, heptyl, tert-butyl,3-methyl-3-pentyl, dicyclopropylmethyl, 2,4-dimethyl-3-pentyl,cyclopentyl, cyclohexyl, allyl, methallyl, 2-methylbut-3-en-2-yl,3-methylbut-2-(prenyl), 3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl,cinnamyl, α-methylcinnamyl, propargyl, phenyl, 2,6-dimethylphenyl,2,6-diisopropylphenyl, 2,6-di-tert-butyl-4-methylphenyl,2,6-di-tert-butyl-4-methoxyphenyl, p-(methylthio)phenyl,pentafluorophenyl, benzyl, triphenylmethyl, diphenylmethyl,bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl.5-dibenzosuberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromonylmethyl, 2,4,6-trimethylbenzyl,p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-Sulfobenzyl,4-azidomethoxybenzyl,4-{N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino}benzyl,piperonyl, 4-picolyl, trimethylsilyl, triethylsilyl,tert-butyldimethylsilyl, isopropyldimethylsilyl, phenyldimethylsilyl,di-tert-butylmethylsilyl, triisopropylsilyl and the like. Other examplesof carboxyl protecting groups are given in Greene and Wutts, above.

The definition of “thiol protecting group” includes but is not limitedto:

I. Alkyl, benzyl, 4-methoxybenzyl, 2-hydroxybenzyl, 4-hydroxybenzyl,2-acetoxybenzyl, 4-acetoxybenzyl, 4-nitrobenzyl, 2,4,6-trimethylbenzyl,2,4,6-trimethoxybenzyl, 4-picolyl, 2-quinolinylmethyl, 2-picolyln-oxido, 9-anthrylmethyl, 9-fluorenylmethyl, xanthenyl, ferrocenylmethyland the like;

II. Diphenylmethyl, bis(4-methoxyphenyl)methyl, 5-dibenzosuberyl,triphenylmethyl, diphenyl-4-pyridylmethyl, phenyl, 2,4-dinitrophenyl,tert-butyl, 1-adamantyl and the like;

III. Methoxymethyl, isobutoxymethyl, benzyloxymethyl,2-tetrahydropyranyl, benzylthiomethyl, phenylthiomethyl,acetamidomethyl, trimethylacetamidomethyl, benzamidomethyl,allyloxycarbonylaminomethyl, phenylacetamidomethyl, phthalimidomethyl,acetyl, carboxy-, cyanomethyl and the like;

IV. (2-nitro-1-phenyl)ethyl, 2-(2,4-dinitrophenyl)ethyl,2-(4′-pyridyl)ethyl, 2-cyanoethyl, 2-(trimethylsilyl)ethyl,2,2-bis(carboethoxy)ethyl, 1-(3-nitrophenyl)-2-benzoylethyl,2-phenylsulfonylethyl, 1-(4-methylphenylsulfonyl)-2-methylpro4-2-yl andthe like;

V. Trimethylsilyl, triethylsilyl, triisopropylsilyl,dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl,tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl,(2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl,tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl and the like;

VI. Benzoyl, trifluoroacetyl,N-[[(4-biphenylyl)isopropoxy]carbonyl]-N-methyl-γ-aminothiobutyrate,N-(t-butoxycarbonyl)-N-methyl-γ-aminothiobutyrate and the like;

VII. 2,2,2-Trichloroethoxycarbonyl, tert-butoxycarbonyl,benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl and the like;

VIII. N-(Ethylamino)carbonyl, N-(methoxymethylamino)carbonyl and thelike;

IX. Ethylthio, tert-butylthio, phenylthio, substituted phenylthio andthe like;

X. (Dimethylphosphino)thioyl, (diphenylphosphino)thioyl and the like;

XI. Sulfonate, alkyloxycarbonylthio, benzyloxycarbonylthio,3-nitro-2-pyridinethio and the like;

XII. Tricarbonyl[1,2,3,4,5-η]-2,4-cyclohexadien-1-yl]-iron(1+) and thelike. Other examples of thiol protecting groups are given in Greene andWutts, above.

The term “amino acid” refers to any of the naturally occurring aminoacids, as well as synthetic analogs and derivatives thereof. Alpha-Aminoacids comprise a carbon atom to which is bonded an amino group, acarboxy group, a hydrogen atom, and a distinctive group referred to as a“side chain”. The side chains of naturally occurring amino acids arewell known in the art and include, for example, hydrogen (e.g., as inglycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine,proline), substituted alkyl (e.g., as in threonine, serine, methionine,cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine,and lysine), arylalkyl (e.g., as in phenylalanine), substitutedarylalkyl (e.g., as in tyrosine), heteroarylalkyl (e.g., as intryptophan, histidine) and the like. One of skill in the art willappreciate that the term “amino acid” can also include beta-, gamma-,delta-, omega-amino acids, and the like. Unnatural amino acids are alsoknown in the art, as set forth in, Natchus, M. G. Organic Synthesis:Theory and Applications (2001), 5, 89-196; Ager, D. J. Current Opinionin Drug Discovery & Development (2001), 4(6), 800; Reginato, G. RecentResearch Developments in Organic Chemistry (2000), 4(Pt. 1), 351-359;Dougherty, D. A. Current Opinion in Chemical Biology (2000), 4(6),645-652; Lesley, S. A. Drugs and the Pharmaceutical Sciences (2000),101(Peptide and Protein Drug Analysis), 191-205; Pojitkov, A. E. Journalof Molecular Catalysis B: Enzymatic (2000), 10(1-3), 47-55; Ager, D. J.Speciality Chemicals (1999), 19(1), 10-12, and all references citedtherein. Stereoisomers (e.g., D-amino acids) of the twenty conventionalamino acids, unnatural amino acids such as alpha, alpha-disubstitutedamino acids and other unconventional amino acids may also be suitablecomponents for compounds of the present invention. Examples ofunconventional amino acids include: 4-hydroxyproline, 3-methylhistidine,5-hydroxylysine, and other similar amino acids and imino acids (e.g.,4-hydroxyproline).

The term “N-protected amino acid” refers to any amino acid which has aprotecting group bound to the nitrogen of the amino functionality. Thisprotecting group prevents reactions from occurring at the aminofunctional group and can be removed by conventional chemical orenzymatic steps to reestablish the amino functional group.

The term “O-protected amino acid” refers to any amino acid which has aprotecting group bound to the oxygen of the carboxyl functionality. Thisprotecting group prevents reactions from occurring at the carboxylfunctional group and can be removed by conventional chemical orenzymatic steps to reestablish the carboxyl functional group. Theparticular protecting group employed is not critical.

The term “prodrug” refers to an agent that is converted into the parentdrug in vivo. Prodrugs are often useful because, in some situations,they may be easier to administer than the parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A prodrug may be converted into theparent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, “Drug Latentiation” in Jucker, ed.Progress in Drug Research 4:221-294 (1962); Morozowich et al.,“Application of Physical Organic Principles to Prodrug Design” in E. B.Roche ed. Design of Biopharmaceutical Properties through Prodrugs andAnalogs, APHA Acad. Pharm. Sci. (1977); Bioreversible Carriers in Drugin Drug Design, Theory and Application, E. B. Roche, ed., APHA Acad.Pharm. Sci. (1987); Design of Prodrugs, H. Bundgaard, Elsevier (1985);Wang et al. “Prodrug approaches to the improved delivery of peptidedrug” in Curr. Pharm. Design. 5(4):265-287 (1999); Pauletti et al.(1997) Improvement in peptide bioavailability: Peptidomimetics andProdrug Strategies, Adv. Drug. Delivery Rev. 27:235-256; Mizen et al.(1998) “The Use of Esters as Prodrugs for Oral Delivery of .beta.-Lactamantibiotics,” Pharm. Biotech. 11, 345-365; Gaignault et al. (1996)“Designing Prodrugs and Bioprecursors I. Carrier Prodrugs,” Pract. Med.Chem. 671-696; Asgharnejad, “Improving Oral Drug Transport”, inTransport Processes in Pharmaceutical Systems, G. L. Amidon, P. I. Leeand E. M. Topp, Eds., Marcell Dekker, p. 185-218 (2000); Balant et al.,“Prodrugs for the improvement of drug absorption via different routes ofadministration”, Eur. J. Drug Metab. Pharmacokinet., 15(2): 143-53(1990); Balimane and Sinko, “Involvement of multiple transporters in theoral absorption of nucleoside analogues”, Adv. Drug Delivery Rev.,39(1-3): 183-209 (1999); Browne, “Fosphenytoin (Cerebyx)”, Clin.Neuropharmacol. 20(1): 1-12 (1997); Bundgaard, “Bioreversiblederivatization of drugs—principle and applicability to improve thetherapeutic effects of drugs”, Arch. Pharm. Chemi 86(1): 1-39 (1979);Bundgaard H. “Improved drug delivery by the prodrug approach”,Controlled Drug Delivery 17: 179-96 (1987); Bundgaard H. “Prodrugs as ameans to improve the delivery of peptide drugs”, Adv. Drug Delivery Rev.8(1): 1-38 (1992); Fleisher et al. “Improved oral drug delivery:solubility limitations overcome by the use of prodrugs”, Adv. DrugDelivery Rev. 19(2): 115-130 (1996); Fleisher et al. “Design of prodrugsfor improved gastrointestinal absorption by intestinal enzymetargeting”, Methods Enzymol. 112 (Drug Enzyme Targeting, Pt. A): 360-81,(1985); Farquhar D, et al., “Biologically ReversiblePhosphate-Protective Groups”, J. Pharm. Sci., 72(3): 324-325 (1983);Freeman S, et al., “Bioreversible Protection for the Phospho Group:Chemical Stability and Bioactivation of Di(4-acetoxy-benzyl)Methylphosphonate with Carboxyesterase,” J. Chem. Soc., Chem. Commun.,875-877 (1991); Friis and Bundgaard, “Prodrugs of phosphates andphosphonates: Novel lipophilic alpha-acyloxyalkyl ester derivatives ofphosphate- or phosphonate containing drugs masking the negative chargesof these groups”, Eur. J. Pharm. Sci. 4: 49-59 (1996); Gangwar et al.,“Pro-drug, molecular structure and percutaneous delivery”, Des.Biopharm. Prop. Prodrugs Analogs, [Symp.] Meeting Date 1976, 409-21.(1977); Nathwani and Wood, “Penicillins: a current review of theirclinical pharmacology and therapeutic use”, Drugs 45(6): 866-94 (1993);Sinhababu and Thakker, “Prodrugs of anticancer agents”, Adv. DrugDelivery Rev. 19(2): 241-273 (1996); Stella et al., “Prodrugs. Do theyhave advantages in clinical practice?”, Drugs 29(5): 455-73 (1985); Tanet al. “Development and optimization of anti-HIV nucleoside analogs andprodrugs: A review of their cellular pharmacology, structure-activityrelationships and pharmacokinetics”, Adv. Drug Delivery Rev. 39(1-3):117-151 (1999); Taylor, “Improved passive oral drug delivery viaprodrugs”, Adv. Drug Delivery Rev., 19(2): 131-148 (1996); Valentino andBorchardt, “Prodrug strategies to enhance the intestinal absorption ofpeptides”, Drug Discovery Today 2(4): 148-155 (1997); Wiebe and Knaus,“Concepts for the design of anti-HIV nucleoside prodrugs for treatingcephalic HIV infection”, Adv. Drug Delivery Rev.: 39(1-3):63-80 (1999);Waller et al., “Prodrugs”, Br. J. Clin. Pharmac. 28: 497-507 (1989).

In light of the purposes described for the present invention, allreferences to reagents ordinarily containing hydrogens, hydrides, orprotons may include partially or fully deuterated versions (containingdeuterium, deuteride, or deuteronium) as required to affecttransformation to the improved drug substances outlined herein.

The term “halogen”, “halide” or “halo” includes fluorine, chlorine,bromine, and iodine.

The terms “alkyl” and “substituted alkyl” are interchangeable andinclude substituted, optionally substituted and unsubstituted C₁-C₁₀straight chain saturated aliphatic hydrocarbon groups, substituted,optionally substituted and unsubstituted C₂-C₁₀ straight chainunsaturated aliphatic hydrocarbon groups, substituted, optionallysubstituted and unsubstituted C₂-C₁₀ branched saturated aliphatichydrocarbon groups, substituted and unsubstituted C₂-C₁₀ branchedunsaturated aliphatic hydrocarbon groups, substituted, optionallysubstituted and unsubstituted C₃-C₈ cyclic saturated aliphatichydrocarbon groups, substituted, optionally substituted andunsubstituted C₅-C₈ cyclic unsaturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, the definitionof “alkyl” shall include but is not limited to: methyl (Me),trideuteromethyl (—CD₃), ethyl (Et), propyl (Pr), butyl (Bu), pentyl,hexyl, heptyl, octyl, nonyl, decyl, undecyl, ethenyl, propenyl, butenyl,penentyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl,isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (t-Bu), sec-butyl (s-Bu),isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, methylcyclopropyl, ethylcyclohexenyl, butenylcyclopentyl,adamantyl, norbornyl and the like. Alkyl substituents are independentlyselected from the group consisting of hydrogen, deuterium, halogen, —OH,—SH, —NH₂, —CN, —NO₂, ═O, ═CH₂, trihalomethyl, carbamoyl,arylC₀₋₁₀alkyl, heteroarylC₀₋₁₀alkyl, C₁₋₁₀alkyloxy, arylC₀₋₁₀alkyloxy,C₁₋₁₀alkylthio, arylC₀₋₁₀alkylthio, C₁₋₁₀alkylamino,arylC₀₋₁₀alkylamino, N-aryl-N—C₀₋₁₀alkylamino, C₁₋₁₀alkylcarbonyl,arylC₀₋₁₀alkylcarbonyl, C₁₋₁₀alkylcarboxy, arylC₀₋₁₀alkylcarboxy,C₁₋₁₀alkylcarbonylamino, arylC₀₋₁₀alkylcarbonylamino, tetrahydrofuryl,morpholinyl, piperazinyl, hydroxypyronyl, —C₀₋₁₀alkylCOOR₃₁ and—C₀₋₁₀alkylCONR₃₂R₃₃ wherein R₃₁, R₃₂ and R₃₃ are independently selectedfrom the group consisting of hydrogen, deuterium, alkyl, aryl, or R₃₂and R₃₃ are taken together with the nitrogen to which they are attachedforming a saturated cyclic or unsaturated cyclic system containing 3 to8 carbon atoms with at least one substituent as defined herein.

In light of the purposes described for the present invention, allreferences to “alkyl” groups or any groups ordinarily containing C—Hbonds may include partially or fully deuterated versions as required toaffect the improvements outlined herein.

The term “alkyloxy” (e.g. methoxy, ethoxy, propyloxy, allyloxy,cyclohexyloxy) represents a substituted or unsubstituted alkyl group asdefined above having the indicated number of carbon atoms attachedthrough an oxygen bridge. The term “alkyloxyalkyl” represents analkyloxy group attached through an alkyl or substituted alkyl group asdefined above having the indicated number of carbon atoms.

The term “alkyloxycarbonyl” (e.g. methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl, allyloxycarbonyl) represents a substituted orunsubstituted alkyloxy group as defined above having the indicatednumber of carbon atoms attached through a carbonyl bridge.

The term “alkylthio” (e.g. methylthio, ethylthio, propylthio,cyclohexenylthio and the like) represents a substituted or unsubstitutedalkyl group as defined above having the indicated number of carbon atomsattached through a sulfur bridge. The term “alkylthioalkyl” representsan alkylthio group attached through an alkyl or substituted alkyl groupas defined above having the indicated number of carbon atoms.

The term “alkylamino” (e.g. methylamino, diethylamino, butylamino,N-propyl-N-hexylamino, (2-cyclopentyl)propylamino, hexenylamino, and thelike) represents one or two substituted or unsubstituted alkyl groups asdefined above having the indicated number of carbon atoms attachedthrough an amine bridge. The substituted or unsubstituted alkyl groupsmaybe taken together with the nitrogen to which they are attachedforming a saturated cyclic or unsaturated cyclic system containing 3 to10 carbon atoms with at least one substituent as defined above. The term“alkylaminoalkyl” represents an alkylamino group attached through asubstituted or unsubstituted alkyl group as defined above having theindicated number of carbon atoms.

The term “alkylhydrazino” (e.g. methylhydrazino, diethylhydrazino,butylhydrazino, (2-cyclopentyl)propylhydrazino, cyclohexanehydrazino,and the like) represents one or two substituted or unsubstituted alkylgroups as defined above having the indicated number of carbon atomsattached through a nitrogen atom of a hydrazine bridge. The substitutedor unsubstituted alkyl groups maybe taken together with the nitrogen towhich they are attached forming a saturated cyclic or unsaturated cyclicsystem containing 3 to 10 carbon atoms with at least one substituent asdefined above. The term “alkylhydrazinoalkyl” represents analkylhydrazino group attached through a substituted or unsubstitutedalkyl group as defined above having the indicated number of carbonatoms.

The term “alkylcarbonyl” (e.g. cyclooctylcarbonyl, pentylcarbonyl,3-hexenylcarbonyl and the like) represents a substituted orunsubstituted alkyl group as defined above having the indicated numberof carbon atoms attached through a carbonyl group. The term“alkylcarbonylalkyl” represents an alkylcarbonyl group attached througha substituted or unsubstituted alkyl group as defined above having theindicated number of carbon atoms.

The term “alkylcarboxy” (e.g. heptylcarboxy, cyclopropylcarboxy,3-pentenylcarboxy and the like) represents an alkylcarbonyl group asdefined above wherein the carbonyl is in turn attached through anoxygen. The term “alkylcarboxyalkyl” represents an alkylcarboxy groupattached through an alkyl group as defined above having the indicatednumber of carbon atoms.

The term “alkylcarbonylamino” (e.g. hexylcarbonylamino,cyclopentylcarbonyl-aminomethyl, methylcarbonylaminophenyl and the like)represents an alkylcarbonyl group as defined above wherein the carbonylis in turn attached through the nitrogen atom of an amino group. Thenitrogen group may itself be substituted with a substituted orunsubstituted alkyl or aryl group. The term “alkylcarbonylaminoalkyl”represents an alkylcarbonylamino group attached through a substituted orunsubstituted alkyl group as defined above having the indicated numberof carbon atoms.

The term “alkylcarbonylhydrazino” (e.g. ethylcarbonylhydrazino,tert-butylcarbonylhydrazino and the like) represents an alkylcarbonylgroup as defined above wherein the carbonyl is in turn attached throughthe nitrogen atom of a hydrazino group.

The term “aryl” represents an unsubstituted, mono-, or polysubstitutedmonocyclic, polycyclic, biaryl aromatic groups covalently attached atany ring position capable of forming a stable covalent bond, certainpreferred points of attachment being apparent to those skilled in theart (e.g., 3-phenyl, 4-naphthyl and the like). The aryl substituents areindependently selected from the group consisting of hydrogen, deuterium,halogen, —OH, —SH, —CN, —NO₂, trihalomethyl, hydroxypyronyl, C₁₋₁₀alkyl,arylC₀₋₁₀alkyl, C₀₋₁₀alkyloxyC₀₋₁₀alkyl, arylC₀₋₁₀alkyloxyC₀₋₁₀alkyl,C₀₋₁₀alkylthioC₀₋₁₀alkyl, arylC₀₋₁₀alkylthioC₀₋₁₀alkyl,C₀₋₁₀alkylaminoC₀₋₁₀alkyl, arylC₀₋₁₀alkylaminoC₀₋₁₀alkyl,N-aryl-N—C₀₋₁₀alkylaminoC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylC₀₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarboxyC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, —C₀₋₁₀alkylCOOR₃₁, and—C₀₋₁₀alkylCONR₃₂R₃₃ wherein R₃₁, R₃₂ and R₃₃ are independently selectedfrom the group consisting of hydrogen, deuterium, alkyl, aryl or R₃₂ andR₃₃ are taken together with the nitrogen to which they are attachedforming a saturated cyclic or unsaturated cyclic system containing 3 to8 carbon atoms with at least one substituent as defined above.

The definition of “aryl” includes but is not limited to phenyl,pentadeuterophenyl, biphenyl, naphthyl, dihydronaphthyl,tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl,fluorenyl, pyrenyl and the like.

The term “arylalkyl” (e.g. (4-hydroxyphenyl)ethyl,(2-aminonaphthyl)hexenyl and the like) represents an aryl group asdefined above attached through a substituted or unsubstituted alkylgroup as defined above having the indicated number of carbon atoms.

The term “arylcarbonyl” (e.g. 2-thiophenylcarbonyl,3-methoxyanthrylcarbonyl and the like) represents an aryl group asdefined above attached through a carbonyl group.

The term “arylalkylcarbonyl” (e.g. (2,3-dimethoxyphenyl)propylcarbonyl,(2-chloronaphthyl)pentenyl-carbonyl and the like) represents anarylalkyl group as defined above wherein the alkyl group is in turnattached through a carbonyl.

The term “aryloxy” (e.g. phenoxy, naphthoxy, 3-methylphenoxy, and thelike) represents an aryl or substituted aryl group as defined abovehaving the indicated number of carbon atoms attached through an oxygenbridge. The term “aryloxyalkyl” represents an aryloxy group attachedthrough a substituted or unsubstituted alkyl group as defined abovehaving the indicated number of carbon atoms.

The term “aryloxycarbonyl” (e.g. phenoxycarbonyl, naphthoxycarbonyl)represents a substituted or unsubstituted aryloxy group as defined abovehaving the indicated number of carbon atoms attached through a carbonylbridge.

The term “arylthio” (e.g. phenylthio, naphthylthio, 3-bromophenylthio,and the like) represents an aryl or substituted aryl group as definedabove having the indicated number of carbon atoms attached through asulfur bridge. The term “arylthioalkyl” represents an arylthio groupattached through a substituted or unsubstituted alkyl group as definedabove having the indicated number of carbon atoms.

The term “arylamino” (e.g. phenylamino, diphenylamino, naphthylamino,N-phenyl-N-naphthylamino, o-methylphenylamino, p-methoxyphenylamino, andthe like) represents one or two aryl groups as defined above having theindicated number of carbon atoms attached through an amine bridge. Theterm “arylaminoalkyl” represents an arylamino group attached through asubstituted or unsubstituted alkyl group as defined above having theindicated number of carbon atoms. The term “arylalkylamino” representsan aryl group attached through an alkylamino group as defined abovehaving the indicated number of carbon atoms. The term“N-aryl-N-alkylamino” (e.g. N-phenyl-N-methylamino,N-naphthyl-N-butylamino, and the like) represents one aryl and one asubstituted or unsubstituted alkyl group as defined above having theindicated number of carbon atoms independently attached through an aminebridge.

The term “arylhydrazino” (e.g. phenylhydrazino, naphthylhydrazino,4-methoxyphenylhydrazino, and the like) represents one or two arylgroups as defined above having the indicated number of carbon atomsattached through a hydrazine bridge. The term “arylhydrazinoalkyl”represents an arylhydrazino group attached through a substituted orunsubstituted alkyl group as defined above having the indicated numberof carbon atoms. The term “arylalkylhydrazino” represents an aryl groupattached through an alkylhydrazino group as defined above having theindicated number of carbon atoms. The term “N-aryl-N-alkylhydrazino”(e.g. N-phenyl-N-methylhydrazino, N-naphthyl-N-butylhydrazino, and thelike) represents one aryl and one a substituted or unsubstituted alkylgroup as defined above having the indicated number of carbon atomsindependently attached through an amine atom of a hydrazine bridge.

The term “arylcarboxy” (e.g. phenylcarboxy, naphthylcarboxy,3-fluorophenylcarboxy and the like) represents an arylcarbonyl group asdefined above wherein the carbonyl is in turn attached through an oxygenbridge. The term “arylcarboxyalkyl” represents an arylcarboxy groupattached through a substituted or unsubstituted alkyl group as definedabove having the indicated number of carbon atoms.

The term “arylcarbonylamino” (e.g. phenylcarbonylamino,naphthylcarbonylamino, 2-methylphenylcarbonylamino and the like)represents an arylcarbonyl group as defined above wherein the carbonylis in turn attached through the nitrogen atom of an amino group. Thenitrogen group may itself be substituted with a substituted orunsubstituted alkyl or aryl group. The term “arylcarbonylaminoalkyl”represents an arylcarbonylamino group attached through a substituted orunsubstituted alkyl group as defined above having the indicated numberof carbon atoms. The Nitrogen group may itself be substituted with asubstituted or unsubstituted alkyl or aryl group.

The term “arylcarbonylhydrazino” (e.g. phenylcarbonylhydrazino,naphthylcarbonylhydrazino, and the like) represents an arylcarbonylgroup as defined above wherein the carbonyl is in turn attached throughthe nitrogen atom of a hydrazino group.

The terms “heteroaryl”, “heterocycle” or “heterocyclic” refers to amonovalent unsaturated group having a single ring or multiple condensedrings, from 1 to 13 carbon atoms and from 1 to 10 hetero atoms selectedfrom the group consisting of nitrogen, sulfur, and oxygen, within thering. The heteroaryl groups in this invention can be optionallysubstituted with 1 to 10 substituents selected from the group consistingof: hydrogen, deuterium, halogen, —OH, —SH, —CN, —NO₂, trihalomethyl,hydroxypyronyl, C₁₋₁₀alkyl, arylC₀₋₁₀alkyl, C₀₋₁₀alkyloxyC₀₋₁₀alkyl,arylC₀₋₁₀alkyloxyC₀₋₁₀alkyl, C₀₋₁₀alkylthioC₀₋₁₀alkyl,arylC₀₋₁₀alkylthioC₀₋₁₀alkyl, CO₀₋₁₀alkylaminoC₀₋₁₀alkyl,arylC₀₋₁₀alkylaminoC₀₋₁₀alkyl, N-aryl-N—C₀₋₁₀alkylaminoC₀₋₁₀alkyl,C₁₋₁₀alkylcarbonylC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarbonylC₀₋₁₀alkyl,C₁₋₁₀alkylcarboxyC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarboxyC₀₋₁₀alkyl,C₁₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, —C₀₋₁₀alkylCOOR₃₁, and—C₀₋₁₀alkylCONR₃₂R₃₃ wherein R₃₁, R₃₂ and R₃₃ are independently selectedfrom the group consisting of hydrogen, deuterium, alkyl, aryl, or R₃₂and R₃₃ are taken together with the nitrogen to which they are attachedforming a saturated cyclic or unsaturated cyclic system containing 3 to8 carbon atoms with at least one substituent as defined above.

The definition of “heteroaryl” includes but is not limited to thienyl,benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl,benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl,pyrrolyl-2,5-dione, 3-pyrrolinyl, indolyl, isoindolyl, 3H-indolyl,indolinyl, indolizinyl, indazolyl, phthalimidyl (orisoindoly-1,3-dione), imidazolyl, 2H-imidazolinyl, benzimidazolyl,deuterobenzimidazolyl, dideuterobenzimidazolyl,trideuterobenzimidazolyl, tetradeuterobenzimidazolyl, pyridyl,deuteropyridyl, dideuteropyridyl, trideuteropyridyl,tetradeuteropyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl,quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl,benzodioxolyl, piperonyl, purinyl, pyrazolyl, triazolyl, tetrazolyl,thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl,benzoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolidinyl-2,5-dione,imidazolidinyl-2,4-dione, 2-thioxo-imidazolidinyl-4-one,imidazolidinyl-2,4-dithione, thiazolidinyl-2,4-dione,4-thioxo-thiazolidinyl-2-one, piperazinyl-2,5-dione,tetrahydro-pyridazinyl-3,6-dione,1,2-dihydro-[1,2,4,5]tetrazinyl-3,6-dione,[1,2,4,5]tetrazinanyl-3,6-dione, dihydro-pyrimidinyl-2,4-dione,pyrimidinyl-2,4,6-trione, 1H-pyrimidinyl-2,4-dione,5-iodo-1H-pyrimidinyl-2,4-dione, 5-chloro-1H-pyrimidinyl-2,4-dione,5-methyl-1H-pyrimidinyl-2,4-dione, 5-isopropyl-1H-pyrimidinyl-2,4-dione,5-propynyl-1H-pyrimidinyl-2,4-dione,5-trifluoromethyl-1H-pyrimidinyl-2,4-dione, 6-amino-9H-purinyl,2-amino-9H-purinyl, 4-amino-1H-pyrimidinyl-2-one,4-amino-5-fluoro-1H-pyrimidinyl-2-one,4-amino-5-methyl-1H-pyrimidinyl-2-one,2-amino-1,9-dihydro-purinyl-6-one, 1,9-dihydro-purinyl-6-one,1H-[1,2,4]triazolyl-3-carboxylic acid amide,2,6-diamino-N6-cyclopropyl-9H-purinyl,2-amino-6-(4-methoxyphenylsulfanyl)-9H-purinyl,5,6-dichloro-1H-benzoimidazolyl,2-isopropylamino-5,6-dichloro-1H-benzoimidazolyl,2-bromo-5,6-dichloro-1H-benzoimidazolyl, 5-methoxy-1H-benzoimidazolyl,3-ethylpyridyl, 5-methyl-2-phenyl-oxazolyl,5-methyl-2-thiophen-2-yl-oxazolyl, 2-furan-2-yl-5-methyl-oxazolyl,3-methyl-3H-quinazolin-4-one, 4-methyl-2H-phthalazin-1-one,2-ethyl-6-methyl-3H-pyrimidin-4-one,5-methoxy-3-methyl-3H-imidazo[4,5-b]pyridine and the like. For thepurposes of this application, the terms “heteroaryl”, “heterocycle” or“heterocyclic” do not include carbohydrate rings (i.e. mono- oroligosaccharides).

The term “saturated heterocyclic” represents an unsubstituted, mono-,and polysubstituted monocyclic, polycyclic saturated heterocyclic groupcovalently attached at any ring position capable of forming a stablecovalent bond, certain preferred points of attachment being apparent tothose skilled in the art (e.g., 1-piperidinyl, 4-piperazinyl, DBU, andthe like).

The saturated heterocyclic substituents are independently selected fromthe group consisting of halo, —OH, —SH, —CN, —NO₂, trihalomethyl,hydroxypyronyl, C₁₋₁₀alkyl, arylC₀₋₁₀alkyl, C₀₋₁₀alkyloxyC₀₋₁₀alkyl,arylC₀₋₁₀alkyloxyC₀₋₁₀alkyl, C₀₋₁₀alkylthioC₀₋₁₀alkyl,arylC₀₋₁₀alkylthioC₀₋₁₀alkyl, C₀₋₁₀alkylaminoC₀₋₁₀alkyl,arylC₀₋₁₀alkylaminoC₀₋₁₀alkyl, N-aryl-N—C₀₋₁₀alkylaminoC₀₋₁₀alkyl,C₁₋₁₀alkylcarbonylC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarbonylC₀₋₁₀alkyl,C₁₋₁₀alkylcarboxyC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarboxyC₀₋₁₀alkyl,C₁₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, —C₀₋₁₀alkylCOOR₃₁, and—C₀₋₁₀alkylCONR₃₂R₃₃ wherein R₃₁, R₃₂ and R₃₃ are independently selectedfrom the group consisting of hydrogen, deuterium, alkyl, aryl, or R₃₂and R₃₃ are taken together with the nitrogen to which they are attachedforming a saturated cyclic or unsaturated cyclic system containing 3 to8 carbon atoms with at least one substituent as defined above.

The definition of saturated heterocyclic includes but is not limited topyrrolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl,1,4-dithienyl, thiomorpholinyl, piperazinyl, quinuclidinyl, and thelike.

The term “alpha-beta-unsaturated carbonyl” refers to a molecule that hasa carbonyl group directly attached to a double or triple bonded carbonand which would be obvious to one of ordinary skill and knowledge in theart. The definition of alpha-beta-unsaturated carbonyl includes but isnot limited to acrolein, methyl vinyl ketone, and the like.

The term “acetal” refers to a molecule that contains a carbon atom C₁that is directly attached to a hydrogen atom (H₁), a substituted carbonatom (C₂) and two oxygen atoms (O₁ and O₂). These oxygen atoms are inturn attached to other substituted carbon atoms (C₃ and C₄), which wouldbe obvious to one of ordinary skill and knowledge in the art. Thedefinition of acetal includes but is not limited to1,1-dimethoxypropane, 1,1-bis-allyloxybutane and the like.

The term “cyclic acetal” refers to an acetal as defined above where C₃and C₄, together with the oxygen atoms to which they are attached,combine thru an alkyl bridge to form a 5- to 10-membered ring, whichwould be obvious to one of ordinary skill and knowledge in the art. Thedefinition of cyclic acetal includes but is not limited to2-methyl-[1,3]dioxolane, 2-ethyl-[1,3]dioxane, 2-phenyl-[1,3]dioxane,2-phenyl-hexahydro-pyrano[3,2-d][1,3]dioxine and the like.

The term “ketal” refers to a molecule that contains a carbon atom C₁that is directly attached to two substituted carbon atom (C₂ and C₃) andtwo oxygen atoms (O₁ and O₂). These oxygen atoms are in turn attached toother substituted carbon atoms (C₄ and C₅), which would be obvious toone of ordinary skill and knowledge in the art. The definition of acetalincludes but is not limited to 2,2-dimethoxy-butane,3,3-diethoxy-pentane and the like.

The term “cyclic ketal” refers to a ketal as defined above where C₄ andC₅, together with the oxygen atoms to which they are attached, combinethru an alkyl bridge to form a 5- to 10-membered ring, which would beobvious to one of ordinary skill and knowledge in the art. Thedefinition of cyclic acetal includes but is not limited to2,2,4,5-tetramethyl-[1,3]dioxolane, 2,2-diethyl-[1,3]dioxepane,2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine and the like.

A “C-carboxy” group refers to a —C(═O)OR groups where R is as definedherein.

An “acetyl” group refers to a —C(═O)CH₃, group.

A “trihalomethanesulfonyl” group refers to a X₃CS(═O)₂— group where X isa halogen.

A “cyano” group refers to a —CN group.

An “isocyanato” group refers to a —NCO group.

A “thiocyanato” group refers to a —CNS group.

An “isothiocyanato” group refers to a —NCS group.

A “sulfinyl” group refers to a —S(═O)—R group, with R as defined herein.

A “S-sulfonamido” group refers to a —S(═O)₂NR, group, with R as definedherein.

A “N-sulfonamido” group refers to a RS(═O)₂NH— group with R as definedherein.

A “trihalomethanesulfonamido” group refers to a X₃CS(═O)₂NR— group withX and R as defined herein.

An “O-carbamyl” group refers to a —OC(═O)—NR, group-with R as definedherein.

An “N-carbamyl” group refers to a ROC(═O)NH— group, with R as definedherein.

An “O-thiocarbamyl” group refers to a —OC(═S)—NR, group with R asdefined herein.

An “N-thiocarbamyl” group refers to an ROC(═S)NH— group, with R asdefined herein.

A “C-amido” group refers to a —C(═O)—NR₂ group with R as defined herein.

An “N-amido” group refers to a RC(═O)NH— group, with R as definedherein.

The term “perhaloalkyl” refers to an alkyl group where all of thehydrogen atoms are replaced by halogen atoms.

The term “pharmaceutical composition” refers to a mixture of a compounddisclosed herein with other chemical components, such as diluents orcarriers. The pharmaceutical composition facilitates administration ofthe compound to an organism. Multiple techniques of administering acompound exist in the art including, but not limited to, oral,injection, aerosol, parenteral, and topical administration.Pharmaceutical compositions can also be obtained by reacting compoundswith inorganic or organic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and thelike.

The term “carrier” defines a chemical compound that facilitates theincorporation of a compound into cells or tissues. For example dimethylsulfoxide (DMSO) is a commonly utilized carrier as it facilitates theuptake of many organic compounds into the cells or tissues of anorganism.

The term “diluent” defines a solution, typically one that is aqueous orpartially aqueous, that dissolves chemical compounds of interest and maystabilize the biologically active form of the compound. Salts dissolvedin buffered solutions are utilized as diluents in the art. One commonlyused buffered solution is phosphate buffered saline because it mimicsthe salt conditions of human blood. Since buffer salts can control thepH of a solution at low concentrations, a buffered diluent rarelymodifies the biological activity of a compound.

Before the present compounds, compositions and methods are disclosed anddescribed, it is to be understood that aspects of the present inventionare not limited to specific synthetic methods, specific pharmaceuticalcarriers, or to particular pharmaceutical formulations or administrationregimens, as such may, of course, vary. It is also to be understood thatthe terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting.

It is also noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a bicyclic aromatic compound” includes mixtures ofbicyclic aromatic compounds; reference to “a pharmaceutical carrier”includes mixtures of two or more such carriers, and the like.

Certain pharmaceutically acceptable salts of the invention are preparedby treating the novel compounds of the invention with an appropriateamount of pharmaceutically acceptable base. Representativepharmaceutically acceptable bases are ammonium hydroxide, sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide,magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copperhydroxide, Aluminum hydroxide, ferric hydroxide, isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine,arginine, histidine, and the like. The reaction is conducted in water orD₂O, alone or in combination with an inert, water-miscible organicsolvent, or in organic solvent alone, at a temperature of from about 0°C. to about 100° C., preferably at room temperature. The molar ratio ofcompounds of structural Formula 1 to base used is chosen to provide theratio desired for any particular salts. For preparing, for example, theammonium salts of the starting material, compounds of Formula 1 can betreated with approximately one equivalent of the pharmaceuticallyacceptable base to yield a neutral salt. When calcium salts areprepared, approximately one-half a molar equivalent of base is used toyield a neutral salt, while for aluminum salts, approximately one-thirda molar equivalent of base will be used.

The compounds of the invention may be conveniently formulated intopharmaceutical compositions composed of one or more of the compoundstogether with a pharmaceutically acceptable carrier as described inRemington's Pharmaceutical Sciences, latest edition, by E. W. Martin(Mack Publ. Co., Easton Pa.).

The compounds of the invention may be administered orally, parenterally(e.g., intravenously), by intramuscular injection, by intraperitonealinjection, topically, transdermally, or the like, although oral ortopical administration is typically preferred. The amount of activecompound administered will, of course, be dependent on the subject beingtreated, the subject's weight, the manner of administration and thejudgment of the prescribing physician. The dosage will be in the rangeof about 1 microgram per kilogram per day to 100 milligram per kilogramper day.

Depending on the intended mode of administration, the pharmaceuticalcompositions may be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, lotions, creams, gels and the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include, as noted above, aneffective amount of the selected drug in combination with apharmaceutically acceptable carrier and, in addition, may include othermedicinal agents, pharmaceutical agents, carriers, adjuvants, diluentsand the like.

For solid compositions, conventional non-toxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmaceuticallyadministrable-compositions can, for example, be prepared by dissolving,dispersing, etc., an active compound as described herein and optionalpharmaceutical adjuvants in an excipient, such as, for example, water,saline, aqueous dextrose, glycerol, ethanol, and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, triethanolamine oleate,etc. Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, referenced above.

For oral administration, fine powders or granules may contain diluting,dispersing, and/or surface active agents, and may be presented in wateror in a syrup, in capsules or sachets in the dry state, or in anon-aqueous solution or suspension wherein suspending agents may beincluded, in tablets wherein binders and lubricants may be included, orin a suspension in water or a syrup. Wherever required, flavoring,preserving, suspending, thickening, or emulsifying agents may also beincluded. Tablets and granules are preferred oral administration forms,and these may be coated.

Parenteral administration, if used, is generally characterized byinjection. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, as emulsions, or as sustainedrelease delivery system.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, bile salts and fusidic acidderivatives. In addition, detergents can be used to facilitatepermeation. Transmucosal administration can be through nasal sprays, forexample, or using suppositories.

For topical administration, the agents are formulated into ointments,creams, salves, powders and gels. In one aspect, the transdermaldelivery agent can be DMSO. Transdermal delivery systems can include,such as for example, patches.

Pharmaceutical compositions containing the compounds of the invention asan active ingredient can take the form of tablets, capsules, powders,suspensions, solutions, emulsions as well as salves and creams, and canbe used for parenteral (intravenous, intradermal, intramuscular,intrathecal etc.) injections, infiltration, topical application, centralinjection at spinal cord, oral, rectal, intravaginal and intranasaladministering or for local application. Such compositions can beprepared by combining the active ingredient(s) with pharmaceuticallyacceptable excipients normally used for this purpose. Such excipientscan comprise aqueous and non-aqueous solvents, stabilizers, suspensionagents, dispersing agents, moisturizers and the like, and will be knownto the skilled person in the pharmaceutical field. The composition mayfurther contain likewise suitable additives such as for instancepolyethylene glycols and, if necessary, colorants, fragrances and thelike.

The pharmaceutical compositions will preferably contain at least about0.1 volume % by weight of the active ingredient. The actualconcentration will depend on the human subject and the chosenadministering route. In general this concentration will lie betweenabout 0.1 and about 100% for the above applications and indications. Thedose of the active ingredient to be administered can further varybetween about 1 microgram and about 100 milligram per kilogram bodyweight per day, preferably between about 1 microgram and 50 milligramper kilogram body weight per day, and most preferably between about 1microgram and 20 milligram per kilogram body weight per day.

The desired dose is preferably presented in the form of one, two, three,four, five, six or more sub-doses that are administered at appropriateintervals per day. The dose or sub-doses can be administered in the formof dosage units containing for instance from 0.5 to 1500 milligram,preferably from 0.5 to 200 milligram and most preferably from 0.5 to 40milligram active constituent per dosage unit, and if the condition ofthe patient requires the dose can, by way of alternative, beadministered as a continuous infusion.

EXAMPLES

As used herein, and unless otherwise indicated, the followingabbreviations have the following meanings: Me refers to methyl (CH₃—),Et refers to ethyl (CH₃CH₂—), i-Pr refers to isopropyl ((CH₃)₂CH₂—),t-Bu or tert-butyl refers to tertiary butyl ((CH₃)₃CH—), Ph refers tophenyl, Bn refers to benzyl (PhCH₂—), Bz refers to benzoyl (PhCO—), MOMrefers to methoxymethyl, Ac refers to acetyl, TMS refers totrimethylsilyl, TBS refers to tert-butyldimethylsilyl, Ms refers tomethanesulfonyl (CH₃SO₂—), Ts refers to p-toluenesulfonyl (p-CH₃PhSO₂—),Tf refers to trifluoromethanesulfonyl (CF₃SO₂—), TfO refers totrifluoromethanesulfonate (CF₃SO₃—), D₂O refers to deuterium oxide, DMFrefers to N,N-dimethylformamide, DCM refers to dichloromethane (CH₂Cl₂),THF refers to tetrahydrofuran, EtOAc refers to ethyl acetate, Et₂Orefers to diethyl ether, MeCN refers to acetonitrile (CH₃CN), NMP refersto 1-N-methyl-2-pyrrolidinone, DMA refers to N,N-dimethylacetamide, DMSOrefers to dimethylsulfoxide, DCC refers to1,3-dicyclohexyldicarbodiimide, EDCI refers to1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, Boc refers totert-butylcarbonyl, Fmoc refers to 9-fluorenylmethoxycarbonyl, TBAFrefers to tetrabutylammonium fluoride, TBAI refers to tetrabutylammoniumiodide, TMEDA refers to N,N,N,N-tetramethylethylene diamine, Dess-Martinperiodinane or Dess Martin reagent refers to1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, DMAP refers to4-N,N-dimethylaminopyridine, (i-Pr)₂NEt or DIEA or Hunig's base refersto N,N-diethylisopropylamine, DBU refers to1,8-Diazabicyclo[5.4.0]undec-7-ene, (DHQ)₂AQN refers to dihydroquinineanthraquinone-1,4-diyl diether, (DHQ)₂PHAL refers to dihydroquininephthalazine-1,4-diyl diether, (DHQ)₂PYR refers to dihydroquinine2,5-diphenyl-4,6-pyrimidinediyl diether, (DHQD)₂AQN refers todihydroquinidine anthraquinone-1,4-diyl diether, (DHQD)₂PHAL refers todihydroquinidine phthalazine-1,4-diyl diether, (DHQD)₂PYR refers todihydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether, LDA refers tolithium diisopropylamide, LiTMP refers to lithium2,2,6,6-tetramethylpiperidinamide, n-BuLi refers to n-butyl lithium,t-BuLi refers to tert-butyl lithium, IBA refers to1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide, OsO₄ refers to osmiumtetroxide, m-CPBA refers to meta-chloroperbenzoic acid, DMD refers todimethyl dioxirane, PDC refers to pyridinium dichromate, NMO refers toN-methyl morpholine-N-oxide, NaHMDS refers to sodiumhexamethyldisilazide, LiHMDS refers to lithium hexamethyldisilazide,HMPA refers to hexamethylphosphoramide, TMSCl refers to trimethylsilylchloride, TMSCN refers to trimethylsilyl cyanide, TBSCl refers totert-butyldimethylsilyl chloride, TFA refers to trifluoroacetic acid,TFAA refers to trifluoroacetic anhydride, AcOH refers to acetic acid,Ac₂O refers to acetic anhydride, AcCl refers to acetyl chloride, TsOHrefers to p-toluenesulfonic acid, TsCl refers to p-toluenesulfonylchloride, MBHA refers to 4-methylbenzhydrylamine, BHA refers tobenzhydrylamine, ZnCl₂ refers to zinc (II) dichloride, BF₃ refers toboron trifluoride, Y(OTf)₂ refers to yttrium (III)trifluoromethanesulfonate, Cu(BF₄)₂ refers to copper (II)tetrafluoroborate, LAH refers to lithium aluminum hydride (LiAlH₄), LADrefers to lithium aluminum deuteride, NaHCO₃ refers to Sodiumbicarbonate, K₂CO₃ refers to Potassium carbonate, NaOH refers to sodiumhydroxide, KOH refers to potassium hydroxide, LiOH refers to lithiumhydroxide, HCl refers to hydrochloric acid, H₂SO₄ refers to sulfuricacid, MgSO₄ refers to magnesium sulfate, and Na₂SO₄ refers to sodiumsulfate. ¹H NMR refers to proton nuclear magnetic resonance, ¹³C NMRrefers to carbon-13 nuclear magnetic resonance, NOE refers to nuclearoverhauser effect, NOESY refers to nuclear overhauser and exchangespectroscopy, COSY refers to homonuclear correlation spectroscopy, HMQCrefers to proton detected heteronuclear multiplet-quantum coherence,HMBC refers to heteronuclear multiple-bond connectivity, s refers tosinglet, br s refers to broad singlet, d refers to doublet, br d refersto broad doublet, t refers to triplet, q refers to quartet, dd refers todouble doublet, m refers to multiplet, ppm refers to parts per million,IR refers to infrared spectrometry, MS refers to mass spectrometry, HRMSrefers to high resolution mass spectrometry, EI refers to electronimpact, FAB refers to fast atom bombardment, CI refers to chemicalionization, HPLC refers to high pressure liquid chromatography, TLCrefer to thin layer chromatography, R_(f) refers to retention factor,R_(t) refers to retention time, GC refers to gas chromatography, min isminutes, h is hours, rt or RT is room or ambient temperature, g isgrams, mg is milligrams, kg is kilograms, L is liters, mL ismilliliters, mol is moles and mmol is millimoles.

For all of the following examples, standard work-up and purificationmethods can be utilized and will be obvious to those skilled in the art.Synthetic methodologies that make up the invention are shown inScheme 1. This scheme is just one of many available literaturepreparative routes and is intended to exemplify the applicable chemistrythrough the use of specific examples and is not indicative of the scopeof the invention.

EXAMPLES

The following non-limiting examples illustrate the inventors' preferredmethods for carrying out the process of the invention.

Example 1 d₉-2-(4-Methoxyphenyl)-acetic acid

d₉-(4-Methoxyphenyl)-acetic acid can be prepared according to knownliterature procedures Ouk et al., Green Chemistry, 2002, 4(5), 431-435,which is hereby incorporated by reference in its entirety, by reactingd₆-(4-hydroxyphenyl)-acetic acid (1 equiv, Cambridge IsotopesLaboratories), K₂CO₃ (0.04 equiv) and d₆-carbonic acid dimethyl ester(1.25 equiv, Cambridge Isotopes Laboratories) at 160° C. untilcompletion.

Example 2 d₁₅-2-(4-Methoxyphenyl)-N,N-dimethyl-acetamide

The title compound is prepared according to the procedure described inYardley et al, Journal of Medicinal Chemistry 1990, 33(10), 2899-2905,which is hereby incorporated by reference in its entirety. A solution ofd₉-(4-methoxyphenyl)-acetic acid (1 equiv) in methylene chloride istreated with oxalyl chloride (1.22 equiv) and DMF (catalytic amount) andthen stirred at room temperature until all acid is converted to the acidchloride. The solvent is removed under reduced pressure and the residueis taken up in methylene chloride and treated with d₆-dimethylaminehydrochloride (1 equiv, Cambridge Isotopes Laboratories), ethyldiisopropylamine (2.1 equiv), and DMAP (0.2 equiv). The mixture isstirred overnight, the solvent is removed under reduced pressure and thecrude residue is purified by silica gel column chromatography.

Example 3d₂₄-2-(1-Hydroxycyclohexyl)-2-(4-methoxyphenyl)-N,N-dimethyl-acetamide

The title compound is prepared according to the procedure described inYardley et al., Journal of Medicinal Chemistry 1990, 33(10), 2899-2905.A solution of d₁₅-2-(4-methoxyphenyl)-N,N-dimethyl-acetamide (1 equiv)in THF is treated with n-butyllithium (1 equiv) at −78° C. The mixtureis stirred for 90 minutes at −78° C.; a THF solution ofd₁₀-cyclohexanone (1.2 equiv, Sigma-Aldrich) is added, and stirring ismaintained until completion. The reaction is quenched by addition of D₂O(2 equiv), the mixture is warmed to room temperature and the solvent isremoved under reduced pressure and the crude residue is purified bysilica gel column chromatography.

Example 4 d₂₆-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol

The title compound is prepared according to the procedure described inYardley et al., Journal of Medicinal Chemistry 1990, 33(10), 2899-2905.d₂₄-2-(1-Hydroxycyclohexyl)-2-(4-methoxyphenyl)-N,N-dimethyl-acetamide(1 equiv) in THF is added dropwise to a mixture of lithium aluminumdeuteride (1.6 equiv) at 0° C. and stirred until completion. Thereaction is quenched with D₂O, and worked up under standard conditionsknown to one skilled in the art. The mixture is then filtered and theprecipitate is washed several times with THF. The combined filtrates areevaporated, and the residue is recrystallized from a suitable solvent.

Example 5 d₃-(4-Methoxyphenyl)-acetonitrile

d₃-Iodomethane (8.70 g, 60 mmol) was added to a stirred solution of(4-hydroxyphenyl)-acetonitrile (4.50 g, 30 mmol) in acetone (30 mL)containing potassium carbonate (6.21 g, 45 mmol) at ambient temperature,and the mixture was heated at reflux overnight, cooled to ambienttemperature, filtered, and concentrated to give the crude product, whichwas purified by flash chromatography using hexanes-ethyl acetate toafford the desired product, d₃-(4-methoxyphenyl)-acetonitrile, as alight yellow oil.

Yield: 3.99 g (89%). ¹H-NMR (CDCl₃) δ ppm: 3.67 (s, 2H), 6.88 (d, 2H,J=8.7 Hz), 7.22 (d, 2H, J=8.7 Hz).

Example 5 d₃-(1-Hydroxycyclohexyl)-(4-methoxyphenyl)-acetonitrile

Tetra-n-butyl ammonium hydrogen sulfate (0.10 g, 0.29 mmol) and 2N NaOH(1.2 mL) were added sequentially to a vigorously stirredd₃-(4-methoxyphenyl)-acetonitrile (0.85 g, 5.66 mmol) at 0° C., andstirring was maintained for 30 minutes. Cyclohexanone (0.67 g, 6.8 mmol)was added to this mixture at 0-5° C. over 10 minute. The reactionmixture was allowed to warm to ambient temperature and vigorous stirringwas continued for an additional 1 hour. The white precipitate wasfiltered and washed with water and hexanes to afford the desiredproduct, d₃-(1-hydroxycyclohexyl)-(4-methoxyphenyl)-acetonitrile, as awhite solid.

Yield: 1.28 g (91%). ¹H-NMR (CDCl₃) δ ppm: 1.05-1.80 (m, 10H), 3.73 (s,1H), 6.90 (d, 2H, J=8.7 Hz), 7.27 (d, 2H, J=8.7 Hz).

Example 6 d₃-1-[2-Amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol

d₃-(1-Hydroxycyclohexyl)-(4-methoxyphenyl)-acetonitrile (400.0 mg, 1.61mmol) was reduced on an H-Cube™ continuous-flow hydrogenation reactor(Thales Nanotechnology, Budapest, Hungary) equipped with a Raney Nicatalyst cartridge (eluent: 2.0M ammonia in methanol, flow rate: 1mL/min, temperature: 80° C., pressure: 80 bar) to yield the desiredproduct, d₃-1-[2-amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol, as aclear colorless oil.

Yield: 280 mg (69%). ¹H-NMR (CDCl₃) δ ppm: 1.05-1.80 (m, 10H), 2.59 (brs, 2H), 2.68 (t, 1H, 6.9 Hz), 3.21 (m, 2H), 6.83 (d, 2H, J=9.0 Hz), 7.17(d, 2H, J=9.0 Hz).

Example 7 d₃-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₃-venlafaxine)

d₃-1-[2-Amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol (207 mg, 0.82mmol), 37% aqueous formaldehyde (0.3 mL), formic acid (0.3 mL) and water(2 mL) were stirred at 80-90° C. for 12 hours, concentrated in vacuo toa volume of 1.5 mL, made basic by the dropwise addition of aqueous 20%sodium hydroxide, and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered and concentratedin vacuo to give a crude residue which was purified by silica gelchromatography (ethyl acetate-methanol-ammonium hydroxide) to give thedesired product,d₃-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol.

Yield: 24.4 mg (11%). ¹H-NMR (methanol-d₄) δ ppm: 0.84-1.54 (m, 10 H),2.42 (s, 6 H), 2.84-2.92 (m, 2 H), 3.26-3.36 (m, 1 H), 6.87 (d, 2 H),7.18 (d, 2 H).

Example 8 d₉-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₉-venlafaxine)

A solution of d₃-1-[2-amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(0.126 g, 0.5 mmol), d₂-formic acid (0.3 mL), and d₂-formaldehyde (20 wt% in D₂O, 0.25 mL) in D₂O (1.5 mL) was heated at 100° C. for 16 hours,cooled to ambient temperature, diluted with water (5 mL), neutralizedwith 35% aqueous ammonia, and extracted with ethyl acetate. The combinedorganic layers were dried over sodium sulfate and concentrated underreduced pressure to yield a crude residue which was purified by flashchromatography (ethyl acetate-methanol-NH₄OH) to give the desiredproduct, d₉-1-[2-methylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol, asa light yellow semi-solid.

Yield: 0.024 g (20%). ¹H-NMR (CDCl₃) δ ppm: 0.78-1.80 (m, 10H), 2.33(dd, 1H, J=12.0, 3.3 Hz), 2.96 (dd, 1H, J=12.0, 3.3 Hz), 3.31 (t, 1H,J=12.0 Hz), 6.81 (d, 2H, J=9.0 Hz), 7.17 (d, 2H, J=9.0 Hz). MS (m/z):287 (M+1).

Example 9 d₁₄-(1-Hydroxycyclohexyl)-(4-methoxyphenyl)-acetonitrile

The title compound was prepared as in Example 5 by substitutingd₁₀-cyclohexanone (Sigma-Aldrich) for cyclohexanone and 2N NaOD in D₂Ofor 2N NaOH in water. The final product was purified byrecrystallization from ethyl acetate-hexanes.

Yield (60%). ¹H-NMR (CDCl₃) δ ppm: 1.60 (br s, 1H), 6.90 (d, 2H, J=8.4Hz), 7.26 (d, 2H, J=8.4 Hz).

Example 10 d₁₄-1-[2-Amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol

d₁₄-(1-Hydroxycyclohexyl)-(4-methoxyphenyl)-acetonitrile (570.0 mg, 2.21mmol) was reduced on an H-Cube™ continuous-flow hydrogenation reactor(Thales Nanotechnology, Budapest, Hungary) equipped with a Raney Nicatalyst cartridge (eluent: 2.0M ammonia in methanol, flow rate: 1mL/min, temperature: 80° C., pressure: 80 bar) to yield the desiredproduct, d₁₄-1-[2-amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol, as aclear colorless oil.

Yield: 530 mg (92%). ¹H-NMR (CDCl₃) δ ppm: 2.62 (br s, 3H), 3.21 (dd,2H), 6.83 (d, 2H), 7.17 (d, 2H).

Example 11d₁₄-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₁₄-venlafaxine)

A solution of d₁₄-1-[2-amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(257.0 mg, 0.98 mmol), formic acid (0.334 mL), and formaldehyde (37% inwater, 0.146 mL) in water (2.32 mL) was stirred at room temperature for45 minutes. Formaldehyde (37% in water, 0.146 mL) was added and themixture was heated to reflux for 17 hours, cooled to room temperature,washed with ethyl acetate, made basic with 20% aqueous sodium hydroxideand extracted with ethyl acetate. The combined organic fractions werewashed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo togive a crude residue which was purified by column chromatography (ethylacetate-methanol-ammonium hydroxide) to give the desired product,d₁₄-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol, as aclear colorless oil.

Yield: 154.4 mg (54%), ¹H-NMR (methanol-d₄) δ ppm: 2.25 (s, 6 H), 2.55(d, 1 H), 3.14 (d, 1 H), 6.84 (d, 2 H), 7.13 (d, 2 H).

Example 12d₂₀-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₂₀-venlafaxine)

The title compound was prepared as in Example 8.

Yield (31%). ¹H-NMR (CDCl₃) δ ppm: 2.33 (d, 1H, J=12.6 Hz), 3.30 (d, 1H,J=12.6 Hz), 6.81 (d, 2H, J=9.0 Hz), 7.05 (d, 2H, J=9.0 Hz). MS (m/z):298 (M+1).

Example 13 In Vitro Liver Microsomal Stability Assay

Liver microsomal stability assays were conducted at 1 mg per mL livermicrosome protein with an NADPH-generating system in 2% NaHCO₃ (2.2 mMNADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphatedehydrogenase and 3.3 mM MgCl₂). Test compounds were prepared assolutions in 20% acetonitrile-water and added to the assay mixture(final assay concentration 5 microgram per mL) and incubated at 37° C.Final concentration of acetonitrile in the assay were <1%. Aliquots (50μL) were taken out at times 0, 15, 30, 45, and 60 minutes, and dilutedwith ice cold acetonitrile (200 μL) to stop the reactions. Samples werecentrifuged at 12000 RPM for 10 minutes to precipitate proteins.Supernatants were transferred to microcentrifuge tubes and stored forLC/MS/MS analysis of the degradation half-life of the test compounds. Ithas thus been found that the compounds of formula (1) according to thepresent invention that have been tested in this assay showed an increaseof 10% or more in the degradation half-life, as compared to thenon-isotopically enriched drug. For example, the degradation half-lifeof d₃-venlafaxine, d₉-venlafaxine, d₁₄-venlafaxine, and d₂₀-venlafaxinewere increased by 50-300% as compared to non-isotopically enrichedvenlafaxine.

Example 14 In Vitro Metabolism Using Human Cytochrome P₄₅₀ Enzymes

The cytochrome P450 enzymes are expressed from the corresponding humancDNA using a baculovirus expression system (BD Biosciences). A 0.25milliliter reaction mixture containing 0.8 milligrams per milliliterprotein, 1.3 millimolar NADP⁺, 3.3 millimolar glucose-6-phosphate, 0.4U/mL glucose-6-phosphate dehydrogenase, 3.3 millimolar magnesiumchloride and 0.2 millimolar of a compound of Formula 1, thecorresponding non-isotopically enriched compound or standard or controlin 100 millimolar potassium phosphate (pH 7.4) is incubated at 37° C.for 20 min. After incubation, the reaction is stopped by the addition ofan appropriate solvent (e.g. acetonitrile, 20% trichloroacetic acid, 94%acetonitrile/6% glacial acetic acid, 70% perchloric acid, 94%acetonitrile/6% glacial acetic acid) and centrifuged (10,000 g) for 3minutes. The supernatant is analyzed by HPLC/MS/MS.

Cytochrome P₄₅₀ Standard CYP1A2 Phenacetin CYP2A6 Coumarin CYP2B6[¹³C]-(S)-mephenytoin CYP2C8 Paclitaxel CYP2C9 Diclofenac CYP2C19[¹³C]-(S)-mephenytoin CYP2D6 (+/−)-Bufuralol CYP2E1 Chlorzoxazone CYP3A4Testosterone CYP4A [¹³C]-Lauric acidPharmacology

The pharmacological profile of compounds of Formula 1 or thecorresponding non-isotopically enriched compounds or standards orcontrols can be demonstrated as follows. The preferred exemplifiedcompounds exhibit a K_(i) value less than 1 micromolar, more preferablyless than 500 nanomolar at the Serotonin transporter as determined usingthe scintillation proximity assay (SPA) described below. See WO2005/060949. Furthermore, the preferred exemplified compoundsselectively inhibit the Serotonin transporter relative to theNorepinephrine and dopamine transporters by a factor of at least fiveusing such SPAs.

Example 15 Generation of Stable Cell Lines Expressing the HumanDopamine, Norepinephrine and Serotonin Transporters

Standard molecular cloning techniques are used to generate stablecell-lines expressing the human Dopamine, Norepinephrine and Serotonintransporters. The polymerase chain reaction (PCR) is used in order toisolate and amplify each of the three full-length cDNAs from anappropriate cDNA library. PCR Primers for the following neurotransmittertransporters are designed using published sequence data. The PCRproducts are cloned into a mammalian expression vector, such as forexample pcDNA3.1 (Invitrogen), using standard ligation techniques,followed by co-transfection of HEK293 cells using a commerciallyavailable lipofection reagent (Lipofectamine™-Invitrogen) following themanufacturer's protocol.

-   -   Human Dopamine transporter: GenBank M95167. Vandenbergh et al,        Molecular Brain Research 1992, 15, 161-166, which is hereby        incorporated by reference in its entirety.    -   Human Norepinephrine transporter: GenBank M65105. Pacholczyk et        al, Nature 1991, 350, 350-354, which is hereby incorporated by        reference in its entirety.    -   Human Serotonin transporter: GenBank L05568. Ramamoorthy et al,        Proceedings of the National Academy of Sciences of the USA 1993,        90, 2542-2546, which is hereby incorporated by reference in its        entirety.

Example 16 In Vitro SPA Binding Assay for the Norepinephrine Transporter

The assay is preformed according to the procedure described in Gobel etal, Journal of Pharmacological and Toxicological Methods 1999, 42(4),237-244, which is hereby incorporated by reference in its entirety.Compound of Formula 1 or the corresponding non-isotopically enrichedcompounds are Serotonin/Norepinephrine reuptake inhibitors;³H-nisoxetine binding to Norepinephrine re-uptake sites in a cell linetransfected with DNA encoding human Norepinephrine transporter bindingprotein has been used to determine the affinity of ligands at theNorepinephrine transporter.

Membrane Preparation

Cell pastes from large scale production of HEK-293 cells expressingcloned human Norepinephrine transporters are homogenized in 4 volumes of50 millimolar Tris-HCl containing 300 millimolar NaCl and 5 millimolarKCl, pH 7.4. The homogenate is centrifuged twice (40,000 g, 10 minutes,4° C.) with pellet re-suspension in 4 volumes of Tris-HCl buffercontaining the above reagents after the first spin, and 8 volumes afterthe second spin. The suspended homogenate is centrifuged (100 g, 10minutes, 4° C.), the supernatant is kept and re-centrifuged (40,000 g,20 minutes, 4° C.). The pellet is re-suspended in Tris-HCl buffercontaining the above reagents along with 10% w/v sucrose and 0.1millimolar phenylmethylsulfonyl fluoride (PMSF). The membranepreparation is stored in aliquots (1.0 milliliter) at −80° C. untilrequired. The protein concentration of the membrane preparation isdetermined using a Bicinchoninic acid (BCA) protein assay reagent kit(available from Pierce).

[³H]-Nisoxetine Binding Assay

Each well of a 96 well microtiter plate is set up to contain 50microliters of 2 nanomolar [N-methyl-3H]-Nisoxetine hydrochloride (70-87Ci/millimole, from NEN Life Science Products), 75 microliters Assaybuffer (50 millimolar Tris-HCl pH 7.4 containing 300 millimolar NaCl and5 millimolar KCl), 25 microliter of diluted compounds of Formula 1 orthe corresponding non-isotopically enriched compounds, assay buffer(total binding) or 10 micromolar Desipramine HCl (non-specific binding),50 microliter wheat germ agglutinin coated poly (vinyltoluene) (WGA PVT)SPA Beads (Amersham Biosciences RPNQ0001) (10 milligram/milliliter), 50microliter membrane (0.2 milligram protein per milliliter). Themicrotiter plates are incubated at room temperature for 10 hours priorto reading in a Trilux scintillation counter. The results are analyzedusing an automatic spline-fitting program (Multicalc, Packard, MiltonKeynes, UK) to provide K_(i) values for each of the test compounds.

Example 17 In Vitro SPA Binding Assay for the Serotonin Transporter

The assay is preformed according to the procedure described inRamamoorthy et al, J. Biol. Chem. 1998, 273(4), 2458-2466, which ishereby incorporated by reference in its entirety. The ability of acompound of Formula 1 or the corresponding non-isotopically enrichedcompound to compete with [³H]-Citalopram for its binding sites on clonedhuman Serotonin transporter containing membranes has been used as ameasure of test compound ability to block Serotonin uptake via itsspecific transporter.

Membrane Preparation

Membrane preparation is essentially similar to that for theNorepinephrine transporter containing membranes as described above. Themembrane preparation is stored in aliquots (1 milliliter) at −70° C.until required. The protein concentration of the membrane preparation isdetermined using a BCA protein assay reagent kit.

[³H]-Citalopram Binding Assay

Each well of a 96 well microtiter plate is set up to contain 50microliters of 2 nanomolar [³H]-Citalopram (60-86 Ci/millimole, AmershamBiosciences), 75 microliters Assay buffer (50 millimolar Tris-HCl pH 7.4containing 150 millimolar NaCl and 5 millimolar KCl), 25 microliters ofdiluted compounds of Formula 1 or the corresponding non-isotopicallyenriched compounds, assay buffer (total binding) or 100 micromolarFluoxetine (non-specific binding), 50 microliters WGA PVT SPA Beads (40milligram/milliliter), 50 microliters membrane preparation (0.4milligram protein per milliliter). The microtiter plates are incubatedat room temperature for 10 hours prior to reading in a Triluxscintillation counter. The results are analyzed using an automaticspline-fitting program (Multicalc, Packard, Milton Keynes, UK) toprovide K_(i) (nanomolar) values for each of the test compounds.

Example 18 In Vitro SPA Binding Assay for the Dopamine Transporter

The assay is preformed according to the procedure described inRamamoorthy et al, J. Biol. Chem. 1998, 273(4), 2458-2466, which ishereby incorporated by reference in its entirety. The ability of a testcompound to compete with [³H]-WIN35,428 for its binding sites on humancell membranes containing cloned human dopamine transporter has beenused as a measure of the ability of such test compounds to blockDopamine uptake via its specific transporter.

Membrane Preparation

Is essentially the same as for membranes containing cloned humanSerotonin transporter as described above.

[³H]-WIN35,428 Binding Assay

Each well of a 96well microtiter plate is set up to contain 50microliters of 4 nanomolar [³H]-WIN35,428 (84-87 Ci/millimole, from NENLife Science Products), 5 microliters Assay buffer (50 millimolarTris-HCl pH 7.4 containing 150 millimolar NaCl and 5 millimolar KCl), 25microliters of diluted compounds of Formula 1 or the correspondingnon-isotopically enriched compounds, assay buffer (total binding) or 100micromolar Nomifensine (non-specific binding), 50 microliters WGA PVTSPA Beads (10 milligram/milliliter), 50 microliters membrane preparation(0.2 milligram protein per milliliter). The microtiter plates areincubated at room temperature for 120 minutes prior to reading in aTrilux scintillation counter. The results are analyzed using anautomatic spline-fitting program (Multicalc, Packard, Milton Keynes, UK)to provide K_(i) values for each of the test compounds.

Example 19 In Vivo Assay for Behavioral Despair in Rats

The assay is performed according to the procedure described in Porsoltet al, Archives Internationales de Pharmacodynamie et de Therapie, 1977,229(2), 327-336, which is hereby incorporated by reference in itsentirety. After intraperitoneal administration of test compound in rats,animals are put in a cylinder containing water for 6 minutes. Immobilitytime is measured during the last 4 minutes. Diminished time ofimmobility is indicative of increased efficacy.

Although the invention has been described with reference to the aboveexamples, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention. Accordingly,the invention is limited only by the following claims.

References Cited—The disclosures of each of the following references areincorporated by reference herein in their entireties.

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What is claimed is:
 1. A compound selected from the group consisting of:

wherein sites designated as D contain deuterium enrichment of at least1%; or a pharmaceutically acceptable salt thereof.
 2. The compound asrecited in claim 1, wherein said compound is the R-enantiomer.
 3. Thecompound as recited in claim 1, wherein said compound is theS-enantiomer.
 4. The compound as recited in claim 1, wherein saidcompound is a hydrochloride salt.
 5. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 6. The pharmaceuticalcomposition as recited in claim 5, formulated as a tablet or capsule. 7.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 2 and a pharmaceuticallyacceptable carrier.
 8. A pharmaceutical composition comprising atherapeutically effective amount of a compound according to claim 3 anda pharmaceutically acceptable carrier.
 9. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound according toclaim 4 and a pharmaceutically acceptable carrier.
 10. The compound asrecited in claim 1 wherein said compound is a mixture of enantiomers.11. The compound as recited in claim 1, wherein sites designated as Dcontain deuterium enrichment of greater than 10%.
 12. The compound asrecited in claim 1, wherein sites designated as D contain deuteriumenrichment of greater than 20%.
 13. The compound as recited in claim 1,wherein sites designated as D contain deuterium enrichment of greaterthan 50%.
 14. The compound as recited in claim 1, wherein sitesdesignated as D contain deuterium enrichment of greater than 70%. 15.The compound as recited in claim 1, wherein sites designated as Dcontain deuterium enrichment of greater than 90%.
 16. The compound asrecited in claim 1, comprising about 10% or less by weight of theS-enantiomer.
 17. The compound as recited in claim 1, comprising about10% or less by weight of the R-enantiomer.